Next Article in Journal / Special Issue
MicroRNAs as New Biomarkers for Diagnosis and Prognosis, and as Potential Therapeutic Targets in Acute Myeloid Leukemia
Previous Article in Journal
Molecular Pharmacology of Rosmarinic and Salvianolic Acids: Potential Seeds for Alzheimer’s and Vascular Dementia Drugs
Previous Article in Special Issue
Corylin Suppresses Hepatocellular Carcinoma Progression via the Inhibition of Epithelial-Mesenchymal Transition, Mediated by Long Noncoding RNA GAS5
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 19
Issue 2
10.3390/ijms19020459
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Epigenetics and MicroRNAs in Cancer

by
Alice Ramassone
1,2,†,
Sara Pagotto
1,2,†,
Angelo Veronese
1,2,* and
Rosa Visone
1,2,*
1
Ageing Research Center and Translational Medicine-CeSI-MeT, 66100 Chieti, Italy
2
Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University Chieti-Pescara, 66100 Chieti, Italy
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(2), 459; https://doi.org/10.3390/ijms19020459
Submission received: 15 January 2018 / Revised: 29 January 2018 / Accepted: 30 January 2018 / Published: 3 February 2018
(This article belongs to the Special Issue Non-Coding RNAs and Epigenetics in Cancer & Selected Papers from the 2nd International Symposium on Frontiers in Molecular Science)
Browse Figures
Versions Notes

Abstract

:
The ability to reprogram the transcriptional circuitry by remodeling the three-dimensional structure of the genome is exploited by cancer cells to promote tumorigenesis. This reprogramming occurs because of hereditable chromatin chemical modifications and the consequent formation of RNA-protein-DNA complexes that represent the principal actors of the epigenetic phenomena. In this regard, the deregulation of a transcribed non-coding RNA may be both cause and consequence of a cancer-related epigenetic alteration. This review summarizes recent findings that implicate microRNAs in the aberrant epigenetic regulation of cancer cells.

Graphical Abstract

1. Introduction

In 1942, Conrad Waddington (1905–1975) introduced for the first time the term “epigenetics” in a paper entitled “The Epigenotype,” defining it as “the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being” [1]. The meaning of this word has gradually evolved since the exponential growth of genetics and in-depth knowledge of this phenomenon. At present, the definition of “epigenetics” as “the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence” is generally accepted [2,3,4,5].
The most common mammalian epigenetic modifications are (i) DNA methylation at the 5-carbon of the cytosine and (ii) histone acetylation and methylation [6,7]. However, it has become evident that (iii) non-coding RNAs have an important role in the molecular mechanisms that sustain epigenetics [8]. Alterations of these factors can cause abnormal epigenetic patterns at canonical promoter boxes or distant regulatory elements and may contribute to deregulate critical genes involved in proliferation, programmed cell death, and cell differentiation [9,10,11].
The initiation and progression of human cancer is thought to be driven by combinations of epigenetic and genetic alterations that activate multistep programs of carcinogenesis [12,13]. Recent evidence shows that epigenetic reprogramming of cancer stem cell (CSC) is a key step in the earliest phases of neoplastic progression. This promotes the clonal expansion of aberrant cells prone to subsequent genetic and epigenetic alterations associated with neoplastic evolution [13,14,15].
Compared to aberrant DNA methylation, little is known about abnormal histone modifications in carcinogenesis, but this is an area of great interest given its importance for chromosome remodeling and, therefore, for transcription regulation, DNA repair, chromosome condensation, and segregation [16,17,18,19,20,21]. Non-coding RNAs can be distinguished in long non-coding RNAs (lncRNAs) and small RNAs including microRNAs, focus of this review. While a role as new epigenetic factors has been assigned to lncRNAs [22,23], microRNAs need a more in-depth discussion.
MicroRNAs (miRNAs or miRs) are small, noncoding RNAs that directly modulate gene expression at the post-transcriptional level binding predominantly to 3′-untranslated region (3′UTR) of target messenger RNAs (mRNAs) in a sequence-specific manner [24,25].
Through this regulation, miRNAs play a pivotal role in several cellular processes, including proliferation, cell cycle control, programmed cell death, differentiation, invasiveness, and tissue specific functions such as immune responses, hormone secretions, and angiogenesis. All these processes are implicated in the development and evolution of cancer [26,27,28,29]. Genome-wide analysis has demonstrated that miRNAs expression is deregulated in most cancer types through various mechanisms, including defects in the miRNA biogenesis machinery, amplification/deletion of the region encompassing the miRNA, or aberrant transcriptional control [26]. Compelling evidence demonstrated that miRNAs can also be deregulated in cancer by abnormal CpGs methylation and/or histone modifications [30]. On the other hand, several miRNAs are not only regulated by epigenetic mechanisms, but themselves have an active role on the epigenetic machinery, creating highly-controlled feedback circuits that finely tune gene expression. These subgroups of miRNAs, called “epi-miRNAs”, are often deregulated in human cancer and target specific epigenetic regulators, such as components of the polycomb repressive complexes 1 and 2 (PRC1 and PRC2), DNA methyl-transferases (DNMTs) and histone deacetylases (HDACs) enzymes, and the Retinoblastoma-Like protein 2 (RBL2) [31,32,33,34,35,36]. Moreover, it was shown that miRNAs are also present in the nucleus [37,38], where they regulate gene expression via distinct mechanisms.
This review summarizes the state-of-the-art of an intimate but still largely unknown networking between epigenetics and microRNAs in human cancer.

2. Epigenetic Alterations of miRNAs in Cancer

2.1. By DNA Methylation

DNA methylation occurs in vertebrate cells at carbon-5 of the cytosine ring in CpG di-nucleotides. The reaction is catalyzed by DNMTs using S-adenosyl-methionine as methyl-donor. It is a normal process used by cells to maintain the physiological expression of genes and to maintain mono-allelic expression of imprinted genes [39]. About 70% of the promoters in the human genome are associated with regions characterized by a high frequency of CpGs (CpG islands, CGIs) that can be methylated by the DNA methylation machinery [40]. In 2007, Weber et al. found that 155 out of 332 human miRNA investigated (47%) were associated with CGIs, suggesting that miRNAs were subject to transcriptional regulation by DNA methylation [41].
The first evidence of regulation of miRNAs by DNA methylation came from a profiling of miRNA expression of the T24 bladder cancer cell line after treatment with the DNA de-methylating agent 5-Aza-2′-deoxycytidine (5-AZA), in combination with an HDAC inhibitor (4-phenylbutyric acid; 4-PBA). Seventeen out of 313 miRNAs were deregulated after treatment. Among these, miR-127 was up-regulated, with consequent down-regulation of its target, the proto-oncogene B-cell lymphoma 6 (BCL6) [42].
In another study, after stable depletion of DNMT1 and DNMT3B in the HCT116 colorectal cancer cell line, the miR-124a, miR-373, and miR-517c were demonstrated to be transcriptionally inactivated by CGI methylation [43]. The same authors also found a signature of microRNA hyper-methylated in metastatic cell lines from colon (SW620), melanoma (IGR37) and head and neck (SIHN-011B) cancers. Hyper-methylation-associated silencing of miR-9, miR-34b/c, and miR-148a observed in those metastatic cell lines was also evident in primary colon, breast, lung, head, and neck carcinomas and melanomas [44].
After these general approaches to identify miRNAs aberrantly expressed by DNA methylation in cancer cells [41,42,43], several tumor specific studies were performed to obtain exploitable data in cancer research.
MiR-9, miR-34b/c, miR-124a, and miR-148a hyper-methylation was confirmed in breast cancer cells [45,46,47], together with let-7a, miR-10b, miR-125b, miR126, miR-152, miR-195/497, miR-200 family, and miRs at the imprinted locus DLK1-DIO3 region [48,49,50,51,52,53,54,55,56]. Moreover, down-regulation by methylation of the miR-149 was reported in clinical cases of chemoresistant breast cancer [57].
In pancreatic ductal adenocarcinoma (PDAC) were found hyper-methylated the miR-9-1, miR-124s, miR-192, miR-615-5p, and miR-1247, suggesting tumor suppressor roles in this type of cancer [58,59,60,61,62]. Differently from breast and other cancers, miR-200a and miR-200b were reported to be expressed and de-methylated in PDAC [63].
In gastric cancer (GC) cell lines and in about 70% of primary GCs the miR-34b/c and the miR-181c genes were found to be epigenetically silenced by CGI hyper-methylation [64]. This was postulated to contribute to the activation of notch 4 (NOTCH4) and KRAS proto-oncogene, GTPase (KRAS), targets of these miRs [65]. Aberrant methylation of the miR-1, miR-9, miR-129, miR-10a/b, of the miR-200a/b/429 locus, and of miR-33b was observed in GC [66,67,68,69,70,71,72]. Of note is the analysis of the methylation status of miR-124 in the normal gastric mucosa of GC patients and healthy volunteers with or without Helicobacter pylori infection. Among the healthy volunteers, the cases with H. pylori infection showed higher levels of methylation of miR-124 than in samples without infection, and among the non-infected samples, gastric mucosa from gastric cancer patients show higher levels of methylation of miR-124 than in the mucosa from healthy donors. These data suggest that the aberrant methylation of miR-124 is an early event in the pathogenesis of GC [73].
In hepatocellular carcinoma (HCC), several miRs were confirmed to be aberrantly methylated such as miR-1, miR-9, miR-34b, miR-124, miR-148a and, miR-200b [74,75,76,77,78]. A microRNA host gene involved in HCC, the insulin like growth factor 2 (IGF2), shows hyper-methylation of 3 CpGs at the intron 2, immediately upstream the miR-483, associated with strong expression of this miR. When methylated, those CpGs cannot bind the transcriptional repressor CCCTC-binding factor (CTCF), permitting microRNA transcription [79]. In the same tumor type, miR-221 is up-regulated [80]. Hypo-methylation of the region upstream miR-221 in a cellular context holding the wild type tumor protein p53 (TP53) seems to enable its expression [81]. A recent study shows a global, cancer-specific microRNA cluster hypo-methylation in HCCs that do not harbor hepatitis C virus (HCV) or hepatitis B virus (HBV) infections [82].
Aberrant methylation of several miRs is a recurrent theme in cancer, which underlines their biological importance in general tumorigenic processes. The miR-9 has been reported aberrantly methylated in ovarian, renal, liver, lung, colorectal cancer, and multiple myeloma. Its silencing allows up-regulation of important oncogenic products, such as cyclin G1 (CCNG1) and epidermal growth factor (EGF) [83]. miR-34s are similarly methylated in several type of cancers, and their silencing affects cellular stemness by targeting CD44 molecule (CD44) and notch 1 (NOTCH1), cell cycle by targeting MYC proto-oncogene, bHLH transcription factor (MYC) and cyclin dependent kinase 6 (CDK6), and apoptosis by targeting BCL2 apoptosis regulator (BCL2) protein[84,85,86,87,88]. Of note is miR-124, whose expression was found to be deregulated by hyper-methylation in 14 different tumor types (Table 1). MiR-124 targets four lncRNAs (metastasis associated lung adenocarcinoma transcript 1 (MALAT1); HOX transcript antisense RNA (HOTAIR); HOXA11 antisense RNA (HOXA11-AS) and long intergenic non-protein coding RNA, regulator of reprogramming (LINC-ROR)) [89,90,91,92] that act as sponges for the miRs, as the miR-124, inhibiting its oncosuppressor functions [93,94,95,96]. MiR-137 was also hyper-methylated in nine different tumor types, which is consistent with the fact that this microRNA controls many cellular processes deregulated in cancer, such as cell cycle progression by targeting CDK6 [97], tumor glutamine metabolism by targeting solute carrier family 1 (neutral amino acid transporter), member 5 (ASCT2) [98], and chromosome remodeling by targeting the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) [99].
MiR-200a/b-429 and miR-200c-141 play a pivotal role in the epithelial to mesenchymal transition (EMT) by targeting the transcription factors zinc finger E-box binding homeobox 1 and 2 (ZEB1; ZEB2) [100,101,102,103], and in cell proliferation by targeting phosphatase and tensin homolog (PTEN) and KRAS [104,105]. These targets play a role also in cellular stemness. Indeed, the stem-like cell fractions isolated from metastatic breast cancers displayed loss of miR-200. Moreover, it has been demonstrated that in the stem-like phenotype, the miR-200c-141 cluster was repressed by promoter CpG hyper-methylation, whereas the miR-200b-200a-429 cluster was silenced through polycomb group-mediated histone modifications [106].

2.2. By Histone Modifications

Histone post-translational modifications include methylation, phosphorylation, acetylation, ubiquitination, and sumoylation. Histone methylation and histone acetylation are covalent post-translational modifications by which methyl or acetyl groups are transferred to amino acids on the histone tails, modifying gene accessibility and hence expression by alteration of the chromatin structure. Specifically, acetylation is associated with an open chromatin state marking active region of transcription, while methylation can be present both in actively transcribed and in repressed regions [107].
The first evidence of deregulation of miRNA due to histone modification in cancer cells was reported by Scott et al. in 2006. These authors demonstrated the aberrant expression of 27 miRNAs after treatment of SKBr3 breast cancer cells with an HDACs inhibitor [108]. In chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), miR-15a and miR-16 are epigenetically silenced due to overexpression of HDACs. Indeed, treatment with a deacetylase inhibitor restored the expression of these miRNAs in CLL cells, with associated down-regulation of MCL-1 levels and decreased CLL cell survival [109,110]. In 2006, Mertens et al. demonstrated that genes at the 13q14.3 region, which harbors miR-15a and miR-16-1, shows mono-allelic expression in B-CLL cells independently of the chromosome copy number. Mono-allelic expression was due to different chromatin packaging of the two copies of 13q14.3; indeed, treatment with 5-aza-CdR or trichostatin A (TSA) induced bi-allelic expression at 13q14.3 [111]. In line with these evidences, we have recently found in CLL a double allele-specific transcriptional regulation of the miR-15a/16-1 cluster involving both the RNA polymerase II and the RNA polymerase III. If either the epigenetic silencing of the 13q14.3 region or the 13q14 deletion affects the allele transcribed by the RNA polymerase II, the allele transcribed by the RNA polymerase III can be un-masked [112]. The oncogenic miR-155 has been found to be epigenetically repressed in breast cancer by BRCA1, DNA repair associated (BRCA1), which recruits HDAC2 on the miR-155 promoter. MiR-155 is up-regulated only in breast cancer cells with loss of wild-type BRCA1 or mutant-BRCA1, since HDCA2 cannot be recruited on the miR promoter [113]. Recent evidence indicates that in prostate cancer, the mocetinostat, a class I selective inhibitor of the HDACs, up-regulates miR-31 with consequent loss of expression of its target E2F transcription factor 6 (E2F6), induction of apoptosis, and reduction in cancer growth [114]. MiR-449 was repressed by HDAC1-3 in HCC cell line [115].
Wang et al. in 2012 demonstrated in HCC that HDAC1 and HDAC3 act as negative regulators of miR-224 expression, whereas the histone acetyl-transferase EP300 is a positive regulator. They suggest that in normal cells, the miR-224 locus is maintained transcriptionally quiescent by HDAC1 and HDAC3, while during cellular transformation, miR-224 expression is activated by overexpression of EP300. Finally, they propose that EP300 could represent a potential drug target to reverse miR-224 overexpression in HCC patients [116].
In 2009, Yang et al. demonstrated that miR-449a/b expression in an osteosarcoma cell line was epigenetically repressed through tri-methylation of the lysine 27 on the histone H3 (H3K27me3), reversible by epigenetic drug treatment [117]. Multiple miRNAs are down-regulated in HCC by EZH2, which mediates H3K27me3, such as miR-139-5p, miR-125b, miR-101, let-7c, and miR-200b [118]. In prostate cancer, miR-181a, miR-181b, miR-200b, miR-200c, and miR-203 were found epigenetically repressed by EZH2 [119]. Recently, miR-31 was also identified to be repressed by EZH2 in prostate cancer [120].
MicroRNAs epigenetically regulated in cancer are reported in Table 1.

3. MiRNAs as Epigenetic Regulators

Although miRNAs are mitotically and meiotically hereditable factors [222,223,224] able to regulate gene expression without involving changes in the DNA sequence, their classification as epigenetic factors is still debated [225]. However, growing evidence shows their substantial role in the control of several canonical epigenetic mechanisms. Specifically, miRNAs regulate at the post-transcriptional level many epigenetic-related-genes (Figure 1). Nevertheless, miRNAs can also act in the nucleus by stimulating or repressing genes transcription in a manner strictly correlated to the chromatin state (Figure 2).

3.1. Post-Transcriptional Gene Silencing by miRNAs

MiRNAs regulate at the post-transcriptional level several epigenetic factors involved in transcriptional regulation, such as DNMTs, PRC1 and PRC2, heterochromatin protein 1 (HP1), and HDACs. Deregulation of these proteins induced by aberrant expression of miRNAs could lead to the epigenetic silencing of tumor suppressor genes, believed to be an early driver of oncogenesis [226].
Deregulation of DNMTs was observed in cancer [227]. The miR-29 family, down-regulated in lung cancer, targets DNA methyl-transferase 3 alpha and 3 beta (DNMT3A-B) [31]. Exogenous expression of miR-29s results in a decrease of global DNA methylation and in the re-expression of tumor suppressor genes in lung cancer and in acute myeloid leukemia [31,32]. Moreover, in hepatocellular carcinoma, miR-29a modulates both the DNA methyl-transferase 1 (DNMT1) and DNMT3B [228]. A DNMT3B splice variant is regulated by miR-148 through the binding to the coding region in cancer cell lines [229]. In cholangiocarcinoma, miR-148a and miR-152 target DNMT1; reduced expression of these miRNAs contributes to increased DNMT1 activity, which affects transcription of the tumor suppressor genes Ras association domain family member 1 (RASSF1A) and cyclin-dependent kinase inhibitor 2A (p16INK4a) [34].
The DNMT family was also found to be regulated by miR-K12-4-5p, which is encoded by Kaposi’s sarcoma-associated herpesvirus (KSHV). miR-K12-4-5p directly down-regulates RBL2, a repressor of DNMT3A-B mRNA transcription [230]. Thus, enforced expression of this viral miRNA reduces RBL2 protein level and increases DNMT1 and DNMT3A-B mRNA levels, leading to global hypo-methylation [33].
PRC2, one of the two classes of Polycomb group proteins was found to cooperate with DNMTs in silencing of target genes [231]. PRC2 mediates the di- and tri-methylation of H3K27 (H3K27me2 and H3K27me3) through the SUZ12 polycomb repressive complex 2 subunit (SUZ12) and EZH2 [232,233], each of which is regulated by miRNAs. For instance, miR-200b negatively regulates the expression of SUZ12 in breast cancer stem cells (BCSC). Loss of miR-200b results in an increase of SUZ12 binding at the E-cadherin (CDH1) promoter, leading to the aberrant H3K27me3 and CDH1 repression. The pathway involving miR-200b, SUZ12, and the CDH1 is important for BCSC growth: induced expression of miR-200b or SUZ12 silencing block tumor formation in in vivo models [234]. In glioma stem-like cells, a tumor subpopulation with self-renewal capacity, down-regulation of SUZ12 depends on miR-128 expression. The restoration of miR-128 affects SUZ12 levels and reduces cell proliferation [235].
EZH2, another member of the PRC2 complex, is over-expressed in cancer, enhancing cell growth and transformation [236,237]. It was found to be regulated by miR-26a and miR-101. miR-26a influences cell cycle progression in Burkitt’ lymphoma cell lines by targeting EZH2 [238], while miR-101 attenuates cell proliferation in bladder transitional carcinoma and prostate cancer cell lines [239,240].
A stable gene silencing is maintained by PRC1, which recognizes H3K27me3, catalyses histone H2A ubiquitylation, and promotes chromatin compactation [241]. It contains several subunits, among which is BMI1 proto-oncogene, polycomb ring finger (BMI1). BMI1 is up-regulated in cancer and promotes stem cell self-renewal [242]. BMI1 expression is controlled by different miRNAs in cancer. In glioma, the miR-128 targets BMI1 leading to reduced self-renewal capacity [243]. In ovarian cancer, BMI1 is regulated by miR-15a and miR-16-1 and induced expression of these miRNAs decreases BMI1 protein levels, reducing ovarian cancer cell proliferation [244]. In endometrial cancer cells, miR-194 negatively regulates BMI1 and reduces cell invasion [245]. By targeting BMI1, miR-218 affects the migration, invasion, and proliferation of glioma cells and blocks self-renewal ability [246]. In multiple myeloma, miR-203 is down-regulated, and its restoration suppresses BMI1 expression and inhibits myeloma cell growth [247].
HDACs interact with PRC2 [248] and are up-regulated in various type of cancer [249]. miR-449a is down-regulated in prostate cancer and its expression negatively correlates with the expression of its direct target, the histone deacetylase 1 (HDAC1); introduction of miR-449a in prostate cancer cells affects cell growth and viability, in part by targeting HDAC1 [250]. However, in different cancer cell models, HDAC1 was demonstrated to act as a repressor of this miR, suggesting a loop that regulates the expression of these genes [115]. In hepatocellular carcinoma, miR-145 is down-regulated and negatively regulates the histone deacetylase 2 (HDAC2) expression. Overexpression of miR-145 reduces the tumorigenic potential of hepatocellular carcinoma cells in vitro and in vivo, recapitulating the effects of HDAC2 inhibition [251]. In B-lymphoma cells the histone deacetylase 4 (HDAC4) is down-regulated by miR-155. In this context, HDAC4 acts as tumor suppressor, reducing proliferation and promoting apoptosis [252].
The HP1 family is involved in several functions, including heterochromatin spread and chromatin condensation [253]. The HP1 family is deregulated in cancer [254]. In colorectal cancer, the HP1γ protein encoded by chromobox 3 gene (CBX3), is overexpressed and associated with poor prognosis, while miR-30a is down-regulated. It was demonstrated that miR-30a targets HP1γ in colon cancer cells inhibiting cell growth and tumour progression in vitro and in vivo [255].
Epigenetic protein factors targeted by miRNAs are shown in Table 2.

3.2. miRNAs Regulate Gene Transcription

Several miRNAs were identified in the nuclear compartment [38]. miR-29b, which is localized in the nucleus, shows in the 3′end a hexanucleotide motif that drives nuclear localization [265]. In this, compartment, miRNAs act on gene promoters, both activating and repressing gene expression (Table 3). Interestingly, the argonaute 1, RISC catalytic component (AGO1), which interacts with miRNAs, was also found to drive transcriptional gene silencing in the nucleus [266,267] or to bind and cooperate with RNA Polymerase II on actively transcribed promoters [268].

3.2.1. MiRNAs Transcriptional Gene Silencing (TGS)

The TGS mechanism mediated by small RNAs was identified in human cells [277]; it involves both AGO1-2 and small interfering RNAs that recognize the target promoter region by sequence complementarity [266,267]. Furthermore, the target region exhibits chromatin markers associated with an inactive state, such as methylation of lysines 27 and 9 of histone H3 (H3K27 and H3K9) [266,278]. Recent studies demonstrated that miRNAs could influence the expression of target genes with similar mechanisms.
MiR-320 was the first identified miRNA able to repress gene transcription. It is located within the RNA polymerase III subunit D (POLR3D) promoter region in antisense orientation. It acts as cis-regulatory element for transcriptional silencing of the POLR3D gene by recruiting AGO1 and EZH2 and causing tri-methylation of the H3K27 on the POLR3D promoter [272]. This epigenetic mechanism could be relevant in cancer since the POLR3D gene product is a component of the RNA polymerase III, whose abnormal activity is characteristic of cancer cells [279].
MiR-10a recognizes a complementary region within the homeobox D4 (HOXD4) promoter and reduces HOXD4 gene expression in breast cancer cells. This mechanism requires the presence of the dicer 1, ribonuclease III protein (DICER) and AGO1-3 and is accompanied by tri-methylation of H3K27 and de novo DNA methylation at target regions [269]. In breast cancer cells, overexpression of a synthetic miR-423-5p inhibits the expression of the Progesterone Receptor (PGR) gene, a prognostic marker of breast cancer [280], by reducing RNA polymerase II binding and enriching silent chromatin markers on PGR gene promoter [274]. In patients with acute myeloid leukemia, miR-223 expression shows an inverse correlation with the expression of NFI-A, a transcription factor whose expression impacts on erythroid or granulocytic lineage commitment [281]. During granulopoiesis induced by retinoic acid, miR-223 represses transcription of nuclear factor I A (NFI-A) by recruiting DICER and the Polycomb group proteins YY1 transcription factor (YY1) and SUZ12 on its promoter to induce a silent chromatin state with the increase of H3K27me3 [271].

3.2.2. MiRNAs Transcriptional Gene Activation (TGA)

MiRNAs are also able to induce gene expression by activating the target gene promoter. This is accompanied by an active chromatin state that includes an increase of di-methylation and tri-methylation of histone H3K4 (H3K4me2 and H3K4me3) and acetylation of histone H3 and H4 (H3ac and H4ac) [282]. MiR-373 is the first discovered miRNA involved in the TGA. In prostate cancer cells, it induces the expression of the tumor suppressor gene CDH1 by complementary binding to its promoter with consequent enrichment of RNA polymerase II on the target promoter [273]. MiR-205 is down-regulated in prostate cancer, and its restoration reduces cell proliferation by activating the interleukin 24 and interleukin 32 (IL24 and IL32) genes. Indeed, miR-205 induces expression of IL24 and IL32 by targeting their promoters, thus leading to an enrichment of RNA polymerase II and of H3ac, H4ac, and H3K4me2 [270]. The miR-483 is encoded within an intron of the IGF2 gene, and overexpression of both IGF2 and miR-483 was observed in Wilms’ tumor [275,283]. MiR-483 up-regulates IGF2 transcription by interacting with the 5′UTR of the transcript and by enhancing the interaction with the RNA helicase DExH-Box Helicase 9 (DHX9) [275], a transcriptional co-activator [284]. The cytochrome c oxidase II (COX2) is a pro-inflammatory gene that shows two complementary sequences for the miR-589 on its promoter: by using an anti-miR-589-5p in lung cancer cells, a reduction of the basal expression of COX2 was observed, while enforced expression of miR-589 results in an increased COX2 protein level [260].
Transcriptional gene activation mediated by miRNAs was also observed in mice: miR-774 and miR-1186 binding sites were identified in the promoter of the cyclin B1 (Ccnb1). The miR-774 recruits AGO1 and promotes the enrichment of the RNA Polymerase II and of the histone H3K4 tri-methylation on Ccnb1 promoter in prostate adenocarcinoma cells [276].

4. Others

With the non-coding RNA world, other areas of research involving the epigenetic phenomena are growing. Recently, the findings of ribonucleoside modifications at RNA-expressed sequences (epi-transcriptome) [285,286] opened a new field of research in cancer biology. Those changes can affect microRNAs maturation influencing expression and downstream targets. A modification able to affect microRNAs processing is methylation of the ribonucleoside adenine (N6-methyladenosine, m6A): the methylated pri-let-7e was processed in pre-let-7e more efficiently than the un-methylated pri-let-7e [287]. Then, it was shown that Adenosine (A) to Inosine (I) editing on miR-200b RNA influences the downstream targeting of the microRNA and, more importantly, correlates with cancer patient prognosis [288].
Another field of research that should be explored is the microRNA targeting the non-coding RNAs involved in chromatin remodeling. It was shown that lncRNAs as H19, imprinted maternally expressed transcript (non-protein coding) (H19) and HOTAIR can act as decoy for microRNAs [89,289,290,291,292], however they also affect chromosome state by binding the epigenetic complex PRC2 [290,293]. It could be possible that the lncRNA-miRNA complexes, other than work as miRNAs decoys, have a functional role in the chromosome remodeling.

5. Conclusions

This review underlines the importance of microRNAs in the complex regulatory mechanisms that control cancer epigenetics. MicroRNAs are tightly regulated by epigenetic modifications such as DNA methylation and histone modifications. However, microRNAs themselves strictly regulate the epigenetic machinery at the post-transcriptional level by establishing epigenetic pathway loops. For instance, overexpression of DNMT1 causes hyper-methylation of miR-148a that, in turn, targets DNMT1 [34,52,261].
As reported, microRNAs can also modulate transcription by binding the promoter of target genes, functioning as a scaffold for chromatin modifiers and transcriptional regulators. The finely-tuned epigenetic network that is unveiling highlights a new level of complexity in the regulation mediated by microRNAs, which modulate at several levels the cellular transcriptome.
Epigenetics changing are reversible, and RNAs are targetable. The possibilities to find useful therapeutic targets in the cancer treatment will increase with future research progress in this area.

Acknowledgments

This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC IG grant 2015-17782 to Rosa Visone) and the Italian Ministry for Health (GR-2011-02350699 to Angelo Veronese).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Waddington, C.H. The epigenotype. Endeavour 1942, 1, 18–20. [Google Scholar] [CrossRef] [PubMed]
  2. Holliday, R. The inheritance of epigenetic defects. Science 1987, 238, 163–170. [Google Scholar] [CrossRef] [PubMed]
  3. Holliday, R. Epigenetics: An overview. Dev. Genet. 1994, 15, 453–457. [Google Scholar] [CrossRef] [PubMed]
  4. Russo, V.E.A.; Martienssen, R.A.; Riggs, A.D. Epigenetic Mechanisms of Gene Regulation; Cold Spring Harbor Laboratory Press: Woodbury, NY, USA, 1996. [Google Scholar]
  5. Wu, C.; Morris, J.R. Genes, genetics, and epigenetics: A correspondence. Science 2001, 293, 1103–1105. [Google Scholar] [CrossRef] [PubMed]
  6. Bannister, A.J.; Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 2011, 21, 381–395. [Google Scholar] [CrossRef] [PubMed]
  7. Mersfelder, E.L.; Parthun, M.R. The tale beyond the tail: Histone core domain modifications and the regulation of chromatin structure. Nucleic Acids Res. 2006, 34, 2653–2662. [Google Scholar] [CrossRef] [PubMed]
  8. Bernstein, E.; Allis, C.D. Rna meets chromatin. Genes Dev. 2005, 19, 1635–1655. [Google Scholar] [CrossRef] [PubMed]
  9. Murtha, M.; Esteller, M. Extraordinary cancer epigenomics: Thinking outside the classical coding and promoter box. Trends Cancer 2016, 2, 572–584. [Google Scholar] [CrossRef] [PubMed]
  10. Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 2008, 358, 1148–1159. [Google Scholar] [CrossRef] [PubMed]
  11. Esteller, M. Aberrant DNA methylation as a cancer-inducing mechanism. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 629–656. [Google Scholar] [CrossRef] [PubMed]
  12. Jones, P.A.; Baylin, S.B. The epigenomics of cancer. Cell 2007, 128, 683–692. [Google Scholar] [CrossRef] [PubMed]
  13. Easwaran, H.; Tsai, H.C.; Baylin, S.B. Cancer epigenetics: Tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol. Cell 2014, 54, 716–727. [Google Scholar] [CrossRef] [PubMed]
  14. Wainwright, E.N.; Scaffidi, P. Epigenetics and cancer stem cells: Unleashing, hijacking, and restricting cellular plasticity. Trends Cancer 2017, 3, 372–386. [Google Scholar] [CrossRef] [PubMed]
  15. Feinberg, A.P.; Ohlsson, R.; Henikoff, S. The epigenetic progenitor origin of human cancer. Nat. Rev. Genet. 2006, 7, 21–33. [Google Scholar] [CrossRef] [PubMed]
  16. Cairns, B.R. The logic of chromatin architecture and remodelling at promoters. Nature 2009, 461, 193–198. [Google Scholar] [CrossRef] [PubMed]
  17. Comet, I.; Riising, E.M.; Leblanc, B.; Helin, K. Maintaining cell identity: PRC2-mediated regulation of transcription and cancer. Nat. Rev. Cancer 2016, 16, 803–810. [Google Scholar] [CrossRef] [PubMed]
  18. Wilson, B.G.; Roberts, C.W. SWI/SNF nucleosome remodellers and cancer. Nat. Rev. Cancer 2011, 11, 481–492. [Google Scholar] [CrossRef] [PubMed]
  19. Lai, A.Y.; Wade, P.A. Cancer biology and nurd: A multifaceted chromatin remodelling complex. Nat. Rev. Cancer 2011, 11, 588–596. [Google Scholar] [CrossRef] [PubMed]
  20. Beck, D.B.; Oda, H.; Shen, S.S.; Reinberg, D. Pr-Set7 and H4K20me1: At the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription. Genes Dev. 2012, 26, 325–337. [Google Scholar] [CrossRef] [PubMed]
  21. Thiagalingam, S.; Cheng, K.H.; Lee, H.J.; Mineva, N.; Thiagalingam, A.; Ponte, J.F. Histone deacetylases: Unique players in shaping the epigenetic histone code. Ann. N. Y. Acad. Sci. 2003, 983, 84–100. [Google Scholar] [CrossRef] [PubMed]
  22. Saxena, A.; Carninci, P. Long non-coding rna modifies chromatin: Epigenetic silencing by long non-coding RNAs. Bioessays 2011, 33, 830–839. [Google Scholar] [CrossRef] [PubMed]
  23. Forrest, M.E.; Khalil, A.M. Review: Regulation of the cancer epigenome by long non-coding RNAs. Cancer Lett. 2017, 407, 106–112. [Google Scholar] [CrossRef] [PubMed]
  24. Ha, M.; Kim, V.N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 2014, 15, 509–524. [Google Scholar] [CrossRef] [PubMed]
  25. He, L.; Hannon, G.J. MicroRNAs: Small RNAs with a big role in gene regulation. Nat. Rev. Genet. 2004, 5, 522–531. [Google Scholar] [CrossRef] [PubMed]
  26. Peng, Y.; Croce, C.M. The role of microRNAs in human cancer. Signal Transduct. Target. Ther. 2016, 1, 15004. [Google Scholar] [CrossRef] [PubMed]
  27. Lovat, F.; Valeri, N.; Croce, C.M. MicroRNAs in the pathogenesis of cancer. Semin. Oncol. 2011, 38, 724–733. [Google Scholar] [CrossRef] [PubMed]
  28. Di Leva, G.; Garofalo, M.; Croce, C.M. MicroRNAs in cancer. Annu. Rev. Pathol. 2014, 9, 287–314. [Google Scholar] [CrossRef] [PubMed]
  29. Garzon, R.; Calin, G.A.; Croce, C.M. MicroRNAs in cancer. Annu. Rev. Med. 2009, 60, 167–179. [Google Scholar] [CrossRef] [PubMed]
  30. Suzuki, H.; Maruyama, R.; Yamamoto, E.; Kai, M. DNA methylation and microRNA dysregulation in cancer. Mol. Oncol. 2012, 6, 567–578. [Google Scholar] [CrossRef] [PubMed]
  31. Fabbri, M.; Garzon, R.; Cimmino, A.; Liu, Z.; Zanesi, N.; Callegari, E.; Liu, S.; Alder, H.; Costinean, S.; Fernandez-Cymering, C.; et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3a and 3b. Proc. Natl. Acad. Sci. USA 2007, 104, 15805–15810. [Google Scholar] [CrossRef] [PubMed]
  32. Garzon, R.; Liu, S.; Fabbri, M.; Liu, Z.; Heaphy, C.E.; Callegari, E.; Schwind, S.; Pang, J.; Yu, J.; Muthusamy, N.; et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 2009, 113, 6411–6418. [Google Scholar] [CrossRef] [PubMed]
  33. Lu, F.; Stedman, W.; Yousef, M.; Renne, R.; Lieberman, P.M. Epigenetic regulation of kaposi’s sarcoma-associated herpesvirus latency by virus-encoded microRNAs that target Rta and the cellular Rbl2-DNMT pathway. J. Virol. 2010, 84, 2697–2706. [Google Scholar] [CrossRef] [PubMed]
  34. Braconi, C.; Huang, N.; Patel, T. MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes. Hepatology 2010, 51, 881–890. [Google Scholar] [CrossRef] [PubMed]
  35. Wellner, U.; Schubert, J.; Burk, U.C.; Schmalhofer, O.; Zhu, F.; Sonntag, A.; Waldvogel, B.; Vannier, C.; Darling, D.; zur Hausen, A.; et al. The emt-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat. Cell Biol. 2009, 11, 1487–1495. [Google Scholar] [CrossRef] [PubMed]
  36. Lei, Q.; Liu, X.; Fu, H.; Sun, Y.; Wang, L.; Xu, G.; Wang, W.; Yu, Z.; Liu, C.; Li, P.; et al. miR-101 reverses hypomethylation of the PRDM16 promoter to disrupt mitochondrial function in astrocytoma cells. Oncotarget 2016, 7, 5007–5022. [Google Scholar] [CrossRef] [PubMed]
  37. Park, C.W.; Zeng, Y.; Zhang, X.; Subramanian, S.; Steer, C.J. Mature microRNAs identified in highly purified nuclei from HCT116 colon cancer cells. RNA Biol. 2010, 7, 606–614. [Google Scholar] [CrossRef] [PubMed]
  38. Liao, J.Y.; Ma, L.M.; Guo, Y.H.; Zhang, Y.C.; Zhou, H.; Shao, P.; Chen, Y.Q.; Qu, L.H. Deep sequencing of human nuclear and cytoplasmic small RNAs reveals an unexpectedly complex subcellular distribution of miRNAs and tRNA 3′ trailers. PLoS ONE 2010, 5, e10563. [Google Scholar] [CrossRef] [PubMed]
  39. Klose, R.J.; Bird, A.P. Genomic DNA methylation: The mark and its mediators. Trends Biochem. Sci. 2006, 31, 89–97. [Google Scholar] [CrossRef] [PubMed]
  40. Saxonov, S.; Berg, P.; Brutlag, D.L. A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc. Natl. Acad. Sci. USA 2006, 103, 1412–1417. [Google Scholar] [CrossRef] [PubMed]
  41. Weber, B.; Stresemann, C.; Brueckner, B.; Lyko, F. Methylation of human microRNA genes in normal and neoplastic cells. Cell Cycle 2007, 6, 1001–1005. [Google Scholar] [CrossRef] [PubMed]
  42. Saito, Y.; Liang, G.; Egger, G.; Friedman, J.M.; Chuang, J.C.; Coetzee, G.A.; Jones, P.A. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 2006, 9, 435–443. [Google Scholar] [CrossRef] [PubMed]
  43. Lujambio, A.; Ropero, S.; Ballestar, E.; Fraga, M.F.; Cerrato, C.; Setien, F.; Casado, S.; Suarez-Gauthier, A.; Sanchez-Cespedes, M.; Git, A.; et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res. 2007, 67, 1424–1429. [Google Scholar] [CrossRef] [PubMed]
  44. Lujambio, A.; Calin, G.A.; Villanueva, A.; Ropero, S.; Sanchez-Cespedes, M.; Blanco, D.; Montuenga, L.M.; Rossi, S.; Nicoloso, M.S.; Faller, W.J.; et al. A microRNA DNA methylation signature for human cancer metastasis. Proc. Natl. Acad. Sci. USA 2008, 105, 13556–13561. [Google Scholar] [CrossRef] [PubMed]
  45. Pronina, I.V.; Loginov, V.I.; Burdennyy, A.M.; Fridman, M.V.; Senchenko, V.N.; Kazubskaya, T.P.; Kushlinskii, N.E.; Dmitriev, A.A.; Braga, E.A. DNA methylation contributes to deregulation of 12 cancer-associated microRNAs and breast cancer progression. Gene 2017, 604, 1–8. [Google Scholar] [CrossRef] [PubMed]
  46. Hsu, P.Y.; Deatherage, D.E.; Rodriguez, B.A.; Liyanarachchi, S.; Weng, Y.I.; Zuo, T.; Liu, J.; Cheng, A.S.; Huang, T.H. Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells. Cancer Res. 2009, 69, 5936–5945. [Google Scholar] [CrossRef] [PubMed]
  47. Lehmann, U.; Hasemeier, B.; Christgen, M.; Muller, M.; Romermann, D.; Langer, F.; Kreipe, H. Epigenetic inactivation of microRNA gene hsa-miR-9-1 in human breast cancer. J. Pathol. 2008, 214, 17–24. [Google Scholar] [CrossRef] [PubMed]
  48. Lu, L.; Katsaros, D.; Zhu, Y.; Hoffman, A.; Luca, S.; Marion, C.E.; Mu, L.; Risch, H.; Yu, H. Let-7a regulation of insulin-like growth factors in breast cancer. Breast Cancer Res. Treat. 2011, 126, 687–694. [Google Scholar] [CrossRef] [PubMed]
  49. Biagioni, F.; Bossel Ben-Moshe, N.; Fontemaggi, G.; Canu, V.; Mori, F.; Antoniani, B.; Di Benedetto, A.; Santoro, R.; Germoni, S.; De Angelis, F.; et al. miR-10b*, a master inhibitor of the cell cycle, is down-regulated in human breast tumours. EMBO Mol. Med. 2012, 4, 1214–1229. [Google Scholar] [CrossRef] [PubMed]
  50. Zhang, Y.; Yan, L.X.; Wu, Q.N.; Du, Z.M.; Chen, J.; Liao, D.Z.; Huang, M.Y.; Hou, J.H.; Wu, Q.L.; Zeng, M.S.; et al. miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer. Cancer Res. 2011, 71, 3552–3562. [Google Scholar] [CrossRef] [PubMed]
  51. Zhang, Y.; Yang, P.; Sun, T.; Li, D.; Xu, X.; Rui, Y.; Li, C.; Chong, M.; Ibrahim, T.; Mercatali, L.; et al. miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nat. Cell Biol. 2013, 15, 284–294. [Google Scholar] [CrossRef] [PubMed]
  52. Xu, Q.; Jiang, Y.; Yin, Y.; Li, Q.; He, J.; Jing, Y.; Qi, Y.T.; Xu, Q.; Li, W.; Lu, B.; et al. A regulatory circuit of miR-148a/152 and DNMT1 in modulating cell transformation and tumor angiogenesis through IGF-IR and IRS1. J. Mol. Cell Biol. 2013, 5, 3–13. [Google Scholar] [CrossRef] [PubMed]
  53. Li, D.; Zhao, Y.; Liu, C.; Chen, X.; Qi, Y.; Jiang, Y.; Zou, C.; Zhang, X.; Liu, S.; Wang, X.; et al. Analysis of miR-195 and miR-497 expression, regulation and role in breast cancer. Clin. Cancer Res. 2011, 17, 1722–1730. [Google Scholar] [CrossRef] [PubMed]
  54. Castilla, M.A.; Diaz-Martin, J.; Sarrio, D.; Romero-Perez, L.; Lopez-Garcia, M.A.; Vieites, B.; Biscuola, M.; RamiRo-Fuentes, S.; Isacke, C.M.; Palacios, J. MicroRNA-200 family modulation in distinct breast cancer phenotypes. PLoS ONE 2012, 7, e47709. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Haga, C.L.; Phinney, D.G. MicroRNAs in the imprinted DLK1-DIO3 region repress the epithelial-to-mesenchymal transition by targeting the TWIST1 protein signaling network. J. Biol. Chem. 2012, 287, 42695–42707. [Google Scholar] [CrossRef] [PubMed]
  56. Lehmann, U. Aberrant DNA methylation of microRNA genes in human breast cancer—A critical appraisal. Cell Tissue Res. 2014, 356, 657–664. [Google Scholar] [CrossRef] [PubMed]
  57. He, D.X.; Gu, X.T.; Li, Y.R.; Jiang, L.; Jin, J.; Ma, X. Methylation-regulated miR-149 modulates chemoresistance by targeting glcnac N-deacetylase/N-sulfotransferase-1 in human breast cancer. FEBS J. 2014, 281, 4718–4730. [Google Scholar] [CrossRef] [PubMed]
  58. Omura, N.; Li, C.P.; Li, A.; Hong, S.M.; Walter, K.; Jimeno, A.; Hidalgo, M.; Goggins, M. Genome-wide profiling of methylated promoters in pancreatic adenocarcinoma. Cancer Biol. Ther. 2008, 7, 1146–1156. [Google Scholar] [CrossRef] [PubMed]
  59. Wang, P.; Chen, L.; Zhang, J.; Chen, H.; Fan, J.; Wang, K.; Luo, J.; Chen, Z.; Meng, Z.; Liu, L. Methylation-mediated silencing of the miR-124 genes facilitates pancreatic cancer progression and metastasis by targeting Rac1. Oncogene 2014, 33, 514–524. [Google Scholar] [CrossRef] [PubMed]
  60. Gao, W.; Gu, Y.; Li, Z.; Cai, H.; Peng, Q.; Tu, M.; Kondo, Y.; Shinjo, K.; Zhu, Y.; Zhang, J.; et al. miR-615-5p is epigenetically inactivated and functions as a tumor suppressor in pancreatic ductal adenocarcinoma. Oncogene 2015, 34, 1629–1640. [Google Scholar] [CrossRef] [PubMed]
  61. Botla, S.K.; Savant, S.; Jandaghi, P.; Bauer, A.S.; Mucke, O.; Moskalev, E.A.; Neoptolemos, J.P.; Costello, E.; Greenhalf, W.; Scarpa, A.; et al. Early epigenetic downregulation of microRNA-192 expression promotes pancreatic cancer progression. Cancer Res. 2016, 76, 4149–4159. [Google Scholar] [CrossRef] [PubMed]
  62. Yi, J.M.; Kang, E.J.; Kwon, H.M.; Bae, J.H.; Kang, K.; Ahuja, N.; Yang, K. Epigenetically altered miR-1247 functions as a tumor suppressor in pancreatic cancer. Oncotarget 2017, 8, 26600–26612. [Google Scholar] [CrossRef] [PubMed]
  63. Li, A.; Omura, N.; Hong, S.M.; Vincent, A.; Walter, K.; Griffith, M.; Borges, M.; Goggins, M. Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels. Cancer Res. 2010, 70, 5226–5237. [Google Scholar] [CrossRef] [PubMed]
  64. Suzuki, H.; Yamamoto, E.; Nojima, M.; Kai, M.; Yamano, H.O.; Yoshikawa, K.; Kimura, T.; Kudo, T.; Harada, E.; Sugai, T.; et al. Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect. Carcinogenesis 2010, 31, 2066–2073. [Google Scholar] [CrossRef] [PubMed]
  65. Hashimoto, Y.; Akiyama, Y.; Otsubo, T.; Shimada, S.; Yuasa, Y. Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis. Carcinogenesis 2010, 31, 777–784. [Google Scholar] [CrossRef] [PubMed]
  66. Tsai, K.W.; Hu, L.Y.; Chen, T.W.; Li, S.C.; Ho, M.R.; Yu, S.Y.; Tu, Y.T.; Chen, W.S.; Lam, H.C. Emerging role of microRNAs in modulating endothelin-1 expression in gastric cancer. Oncol. Rep. 2015, 33, 485–493. [Google Scholar] [CrossRef] [PubMed]
  67. Tsai, K.W.; Liao, Y.L.; Wu, C.W.; Hu, L.Y.; Li, S.C.; Chan, W.C.; Ho, M.R.; Lai, C.H.; Kao, H.W.; Fang, W.L.; et al. Aberrant hypermethylation of miR-9 genes in gastric cancer. Epigenetics 2011, 6, 1189–1197. [Google Scholar] [CrossRef] [PubMed]
  68. Tsai, K.W.; Wu, C.W.; Hu, L.Y.; Li, S.C.; Liao, Y.L.; Lai, C.H.; Kao, H.W.; Fang, W.L.; Huang, K.H.; Chan, W.C.; et al. Epigenetic regulation of miR-34b and miR-129 expression in gastric cancer. Int. J. Cancer 2011, 129, 2600–2610. [Google Scholar] [CrossRef] [PubMed]
  69. Jia, H.; Zhang, Z.; Zou, D.; Wang, B.; Yan, Y.; Luo, M.; Dong, L.; Yin, H.; Gong, B.; Li, Z.; et al. microRNA-10a is down-regulated by DNA methylation and functions as a tumor suppressor in gastric cancer cells. PLoS ONE 2014, 9, e88057. [Google Scholar] [CrossRef] [PubMed]
  70. Li, Z.; Lei, H.; Luo, M.; Wang, Y.; Dong, L.; Ma, Y.; Liu, C.; Song, W.; Wang, F.; Zhang, J.; et al. DNA methylation downregulated miR-10b acts as a tumor suppressor in gastric cancer. Gastric Cancer 2015, 18, 43–54. [Google Scholar] [CrossRef] [PubMed]
  71. Ning, X.; Shi, Z.; Liu, X.; Zhang, A.; Han, L.; Jiang, K.; Kang, C.; Zhang, Q. DNMT1 and EZH2 mediated methylation silences the microRNA-200b/a/429 gene and promotes tumor progression. Cancer Lett. 2015, 359, 198–205. [Google Scholar] [CrossRef] [PubMed]
  72. Yin, H.; Song, P.; Su, R.; Yang, G.; Dong, L.; Luo, M.; Wang, B.; Gong, B.; Liu, C.; Song, W.; et al. DNA methylation mediated down-regulating of microRNA-33b and its role in gastric cancer. Sci. Rep. 2016, 6, 18824. [Google Scholar] [CrossRef] [PubMed]
  73. Ando, T.; Yoshida, T.; Enomoto, S.; Asada, K.; Tatematsu, M.; Ichinose, M.; Sugiyama, T.; Ushijima, T. DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: Its possible involvement in the formation of epigenetic field defect. Int. J. Cancer 2009, 124, 2367–2374. [Google Scholar] [CrossRef] [PubMed]
  74. Datta, J.; Kutay, H.; Nasser, M.W.; Nuovo, G.J.; Wang, B.; Majumder, S.; Liu, C.G.; Volinia, S.; Croce, C.M.; Schmittgen, T.D.; et al. Methylation mediated silencing of microRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res. 2008, 68, 5049–5058. [Google Scholar] [CrossRef] [PubMed]
  75. Zhang, J.; Cheng, J.; Zeng, Z.; Wang, Y.; Li, X.; Xie, Q.; Jia, J.; Yan, Y.; Guo, Z.; Gao, J.; et al. Comprehensive profiling of novel microRNA-9 targets and a tumor suppressor role of microRNA-9 via targeting IGF2BP1 in hepatocellular carcinoma. Oncotarget 2015, 6, 42040–42052. [Google Scholar] [CrossRef] [PubMed]
  76. Xie, K.; Liu, J.; Chen, J.; Dong, J.; Ma, H.; Liu, Y.; Hu, Z. Methylation-associated silencing of microRNA-34b in hepatocellular carcinoma cancer. Gene 2014, 543, 101–107. [Google Scholar] [CrossRef] [PubMed]
  77. Furuta, M.; Kozaki, K.I.; Tanaka, S.; Arii, S.; Imoto, I.; Inazawa, J. miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma. Carcinogenesis 2010, 31, 766–776. [Google Scholar] [CrossRef] [PubMed]
  78. He, X.X.; Kuang, S.Z.; Liao, J.Z.; Xu, C.R.; Chang, Y.; Wu, Y.L.; Gong, J.; Tian, D.A.; Guo, A.Y.; Lin, J.S. The regulation of microRNA expression by DNA methylation in hepatocellular carcinoma. Mol. Biosyst. 2015, 11, 532–539. [Google Scholar] [CrossRef] [PubMed]
  79. Veronese, A.; Visone, R.; Consiglio, J.; Acunzo, M.; Lupini, L.; Kim, T.; Ferracin, M.; Lovat, F.; Miotto, E.; Balatti, V.; et al. Mutated beta-catenin evades a microRNA-dependent regulatory loop. Proc. Natl. Acad. Sci. USA 2011, 108, 4840–4845. [Google Scholar] [CrossRef] [PubMed]
  80. Callegari, E.; Elamin, B.K.; Giannone, F.; Milazzo, M.; Altavilla, G.; Fornari, F.; Giacomelli, L.; D’Abundo, L.; Ferracin, M.; Bassi, C.; et al. Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model. Hepatology 2012, 56, 1025–1033. [Google Scholar] [CrossRef] [PubMed]
  81. Fornari, F.; Milazzo, M.; Galassi, M.; Callegari, E.; Veronese, A.; Miyaaki, H.; Sabbioni, S.; Mantovani, V.; Marasco, E.; Chieco, P.; et al. P53/mdm2 feedback loop sustains miR-221 expression and dictates the response to anticancer treatments in hepatocellular carcinoma. Mol. Cancer Res. MCR 2014, 12, 203–216. [Google Scholar] [CrossRef] [PubMed]
  82. Nojima, M.; Matsui, T.; Tamori, A.; Kubo, S.; Shirabe, K.; Kimura, K.; Shimada, M.; Utsunomiya, T.; Kondo, Y.; Iio, E.; et al. Global, cancer-specific microRNA cluster hypomethylation was functionally associated with the development of non-b non-c hepatocellular carcinoma. Mol. Cancer 2016, 15, 31. [Google Scholar] [CrossRef] [PubMed]
  83. Selcuklu, S.D.; Donoghue, M.T.; Rehmet, K.; de Souza Gomes, M.; Fort, A.; Kovvuru, P.; Muniyappa, M.K.; Kerin, M.J.; Enright, A.J.; Spillane, C. MicroRNA-9 inhibition of cell proliferation and identification of novel miR-9 targets by transcriptome profiling in breast cancer cells. J. Biol. Chem. 2012, 287, 29516–29528. [Google Scholar] [CrossRef] [PubMed]
  84. Liu, C.; Kelnar, K.; Liu, B.; Chen, X.; Calhoun-Davis, T.; Li, H.; Patrawala, L.; Yan, H.; Jeter, C.; Honorio, S.; et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat. Med. 2011, 17, 211–215. [Google Scholar] [CrossRef] [PubMed]
  85. Park, E.Y.; Chang, E.; Lee, E.J.; Lee, H.W.; Kang, H.G.; Chun, K.H.; Woo, Y.M.; Kong, H.K.; Ko, J.Y.; Suzuki, H.; et al. Targeting of miR34a-NOTCH1 axis reduced breast cancer stemness and chemoresistance. Cancer Res. 2014, 74, 7573–7582. [Google Scholar] [CrossRef] [PubMed]
  86. Bu, P.; Chen, K.Y.; Chen, J.H.; Wang, L.; Walters, J.; Shin, Y.J.; Goerger, J.P.; Sun, J.; Witherspoon, M.; Rakhilin, N.; et al. A microRNA miR-34a-regulated bimodal switch targets notch in colon cancer stem cells. Cell Stem Cell 2013, 12, 602–615. [Google Scholar] [CrossRef] [PubMed]
  87. Cama, A.; Verginelli, F.; Lotti, L.V.; Napolitano, F.; Morgano, A.; D’Orazio, A.; Vacca, M.; Perconti, S.; Pepe, F.; Romani, F.; et al. Integrative genetic, epigenetic and pathological analysis of paraganglioma reveals complex dysregulation of notch signaling. Acta Neuropathol. 2013, 126, 575–594. [Google Scholar] [CrossRef] [PubMed]
  88. Hermeking, H. The miR-34 family in cancer and apoptosis. Cell Death Differ. 2010, 17, 193–199. [Google Scholar] [CrossRef] [PubMed]
  89. Liu, X.H.; Sun, M.; Nie, F.Q.; Ge, Y.B.; Zhang, E.B.; Yin, D.D.; Kong, R.; Xia, R.; Lu, K.H.; Li, J.H.; et al. Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol. Cancer 2014, 13. [Google Scholar] [CrossRef] [PubMed]
  90. Liu, S.; Song, L.; Zeng, S.; Zhang, L. MALAT1-miR-124-RBG2 axis is involved in growth and invasion of HR-HPV-positive cervical cancer cells. Tumour Biol. 2016, 37, 633–640. [Google Scholar] [CrossRef] [PubMed]
  91. Lu, Q.; Zhao, N.; Zha, G.; Wang, H.; Tong, Q.; Xin, S. LncRNA HOXA11-AS exerts oncogenic functions by repressing p21 and miR-124 in uveal melanoma. DNA Cell Biol. 2017, 36, 837–844. [Google Scholar] [CrossRef] [PubMed]
  92. Li, C.; Zhao, Z.; Zhou, Z.; Liu, R. Linc-ROR confers gemcitabine resistance to pancreatic cancer cells via inducing autophagy and modulating the miR-124/PTBP1/PKM2 axis. Cancer Chemother. Pharmacol. 2016, 78, 1199–1207. [Google Scholar] [CrossRef] [PubMed]
  93. Anastasiadou, E.; Jacob, L.S.; Slack, F.J. Non-coding rna networks in cancer. Nat. Rev. Cancer 2018, 18, 5–18. [Google Scholar] [CrossRef] [PubMed]
  94. Sun, M.; Nie, F.; Wang, Y.; Zhang, Z.; Hou, J.; He, D.; Xie, M.; Xu, L.; De, W.; Wang, Z.; et al. LncRNA HOXA11-AS promotes proliferation and invasion of gastric cancer by scaffolding the chromatin modification factors PRC2, LSD1, and DNMT1. Cancer Res. 2016, 76, 6299–6310. [Google Scholar] [CrossRef] [PubMed]
  95. Hou, P.; Zhao, Y.; Li, Z.; Yao, R.; Ma, M.; Gao, Y.; Zhao, L.; Zhang, Y.; Huang, B.; Lu, J. LincRNA-ror induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis. 2014, 5, e1287. [Google Scholar] [CrossRef] [PubMed]
  96. Li, C.; Lu, L.; Feng, B.; Zhang, K.; Han, S.; Hou, D.; Chen, L.; Chu, X.; Wang, R. The lincRNA-ROR/miR-145 axis promotes invasion and metastasis in hepatocellular carcinoma via induction of epithelial-mesenchymal transition by targeting ZEB2. Sci. Rep. 2017, 7, 4637. [Google Scholar] [CrossRef] [PubMed]
  97. Zhu, X.; Li, Y.; Shen, H.; Li, H.; Long, L.; Hui, L.; Xu, W. miR-137 inhibits the proliferation of lung cancer cells by targeting Cdc42 and Cdk6. FEBS Lett. 2013, 587, 73–81. [Google Scholar] [CrossRef] [PubMed]
  98. Dong, J.; Xiao, D.; Zhao, Z.; Ren, P.; Li, C.; Hu, Y.; Shi, J.; Su, H.; Wang, L.; Liu, H.; et al. Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism. Oncogenesis 2017, 6, e356. [Google Scholar] [CrossRef] [PubMed]
  99. Sun, J.; Zheng, G.; Gu, Z.; Guo, Z. miR-137 inhibits proliferation and angiogenesis of human glioblastoma cells by targeting EZH2. J. Neurooncol. 2015, 122, 481–489. [Google Scholar] [CrossRef] [PubMed]
  100. Xia, H.; Ng, S.S.; Jiang, S.; Cheung, W.K.; Sze, J.; Bian, X.W.; Kung, H.F.; Lin, M.C. miR-200a-mediated downregulation of ZEB2 and CTNNB1 differentially inhibits nasopharyngeal carcinoma cell growth, migration and invasion. Biochem. Biophys. Res. Commun. 2010, 391, 535–541. [Google Scholar] [CrossRef] [PubMed]
  101. Park, S.M.; Gaur, A.B.; Lengyel, E.; Peter, M.E. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the e-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008, 22, 894–907. [Google Scholar] [CrossRef] [PubMed]
  102. Gregory, P.A.; Bert, A.G.; Paterson, E.L.; Barry, S.C.; Tsykin, A.; Farshid, G.; Vadas, M.A.; Khew-Goodall, Y.; Goodall, G.J. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 2008, 10, 593–601. [Google Scholar] [CrossRef] [PubMed]
  103. Kim, T.; Veronese, A.; Pichiorri, F.; Lee, T.J.; Jeon, Y.J.; Volinia, S.; Pineau, P.; Marchio, A.; Palatini, J.; Suh, S.S.; et al. P53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J. Exp. Med. 2011, 208, 875–883. [Google Scholar] [CrossRef] [PubMed]
  104. Li, H.; Tang, J.; Lei, H.; Cai, P.; Zhu, H.; Li, B.; Xu, X.; Xia, Y.; Tang, W. Decreased miR-200a/141 suppress cell migration and proliferation by targeting pten in hirschsprung’s disease. Cell Physiol. Biochem. 2014, 34, 543–553. [Google Scholar] [CrossRef] [PubMed]
  105. Kopp, F.; Wagner, E.; Roidl, A. The proto-oncogene kras is targeted by miR-200c. Oncotarget 2014, 5, 185–195. [Google Scholar] [CrossRef] [PubMed]
  106. Lim, Y.Y.; Wright, J.A.; Attema, J.L.; Gregory, P.A.; Bert, A.G.; Smith, E.; Thomas, D.; Lopez, A.F.; Drew, P.A.; Khew-Goodall, Y.; et al. Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-cell-like state. J. Cell Sci. 2013, 126, 2256–2266. [Google Scholar] [CrossRef] [PubMed]
  107. Jenuwein, T. Re-set-ting heterochromatin by histone methyltransferases. Trends Cell Biol. 2001, 11, 266–273. [Google Scholar] [CrossRef]
  108. Scott, G.K.; Mattie, M.D.; Berger, C.E.; Benz, S.C.; Benz, C.C. Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res. 2006, 66, 1277–1281. [Google Scholar] [CrossRef] [PubMed]
  109. Sampath, D.; Liu, C.; Vasan, K.; Sulda, M.; Puduvalli, V.K.; Wierda, W.G.; Keating, M.J. Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia. Blood 2012, 119, 1162–1172. [Google Scholar] [CrossRef] [PubMed]
  110. Zhang, X.; Chen, X.; Lin, J.; Lwin, T.; Wright, G.; Moscinski, L.C.; Dalton, W.S.; Seto, E.; Wright, K.; Sotomayor, E.; et al. Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-hodgkin b-cell lymphomas. Oncogene 2012, 31, 3002–3008. [Google Scholar] [CrossRef] [PubMed]
  111. Mertens, D.; Wolf, S.; Tschuch, C.; Mund, C.; Kienle, D.; Ohl, S.; Schroeter, P.; Lyko, F.; Dohner, H.; Stilgenbauer, S.; et al. Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism. Proc. Natl. Acad. Sci. USA 2006, 103, 7741–7746. [Google Scholar] [CrossRef] [PubMed]
  112. Veronese, A.; Pepe, F.; Chiacchia, J.; Pagotto, S.; Lanuti, P.; Veschi, S.; Di Marco, M.; D’Argenio, A.; Innocenti, I.; Vannata, B.; et al. Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia. Leukemia 2015, 29, 86–95. [Google Scholar] [CrossRef] [PubMed]
  113. Chang, S.; Wang, R.H.; Akagi, K.; Kim, K.A.; Martin, B.K.; Cavallone, L.; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab); Haines, D.C.; Basik, M.; Mai, P.; et al. Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155. Nat. Med. 2011, 17, 1275–1282. [Google Scholar] [CrossRef] [PubMed]
  114. Zhang, Q.; Sun, M.; Zhou, S.; Guo, B. Class I HDAC inhibitor mocetinostat induces apoptosis by activation of miR-31 expression and suppression of E2F6. Cell Death Discov. 2016, 2, 16036. [Google Scholar] [CrossRef] [PubMed]
  115. Buurman, R.; Gurlevik, E.; Schaffer, V.; Eilers, M.; Sandbothe, M.; Kreipe, H.; Wilkens, L.; Schlegelberger, B.; Kuhnel, F.; Skawran, B. Histone deacetylases activate hepatocyte growth factor signaling by repressing microRNA-449 in hepatocellular carcinoma cells. Gastroenterology 2012, 143, 811–820. [Google Scholar] [CrossRef] [PubMed]
  116. Wang, Y.; Toh, H.C.; Chow, P.; Chung, A.Y.; Meyers, D.J.; Cole, P.A.; Ooi, L.L.; Lee, C.G. MicroRNA-224 is up-regulated in hepatocellular carcinoma through epigenetic mechanisms. FASEB J. 2012, 26, 3032–3041. [Google Scholar] [CrossRef] [PubMed]
  117. Yang, X.; Feng, M.; Jiang, X.; Wu, Z.; Li, Z.; Aau, M.; Yu, Q. miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate PRB-E2F1 activity through a feedback loop by targeting CDK6 and CDC25a. Genes Dev. 2009, 23, 2388–2393. [Google Scholar] [CrossRef] [PubMed]
  118. Au, S.L.; Wong, C.C.; Lee, J.M.; Fan, D.N.; Tsang, F.H.; Ng, I.O.; Wong, C.M. Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatology 2012, 56, 622–631. [Google Scholar] [CrossRef] [PubMed]
  119. Cao, Q.; Mani, R.S.; Ateeq, B.; Dhanasekaran, S.M.; Asangani, I.A.; Prensner, J.R.; Kim, J.H.; Brenner, J.C.; Jing, X.; Cao, X.; et al. Coordinated regulation of polycomb group complexes through microRNAs in cancer. Cancer Cell 2011, 20, 187–199. [Google Scholar] [CrossRef] [PubMed]
  120. Zhang, Q.; Padi, S.K.; Tindall, D.J.; Guo, B. Polycomb protein EZH2 suppresses apoptosis by silencing the proapoptotic miR-31. Cell Death Dis. 2014, 5, e1486. [Google Scholar] [CrossRef] [PubMed]
  121. Chen, W.S.; Leung, C.M.; Pan, H.W.; Hu, L.Y.; Li, S.C.; Ho, M.R.; Tsai, K.W. Silencing of miR-1-1 and miR-133a-2 cluster expression by DNA hypermethylation in colorectal cancer. Oncol. Rep. 2012, 28, 1069–1076. [Google Scholar] [CrossRef] [PubMed]
  122. Nasser, M.W.; Datta, J.; Nuovo, G.; Kutay, H.; Motiwala, T.; Majumder, S.; Wang, B.; Suster, S.; Jacob, S.T.; Ghoshal, K. Down-regulation of micro-RNA-1 (miR-1) in lung cancer. Suppression of tumorigenic property of lung cancer cells and their sensitization to doxorubicin-induced apoptosis by miR-1. J. Biol. Chem. 2008, 283, 33394–33405. [Google Scholar] [CrossRef] [PubMed]
  123. Li, X.; Pan, Q.; Wan, X.; Mao, Y.; Lu, W.; Xie, X.; Cheng, X. Methylation-associated has-miR-9 deregulation in paclitaxel-resistant epithelial ovarian carcinoma. BMC Cancer 2015, 15, 509. [Google Scholar] [CrossRef] [PubMed]
  124. Zhang, Q.; Wang, L.Q.; Wong, K.Y.; Li, Z.Y.; Chim, C.S. Infrequent DNA methylation of miR-9-1 and miR-9-3 in multiple myeloma. J. Clin. Pathol. 2015, 68, 557–561. [Google Scholar] [CrossRef] [PubMed]
  125. Hildebrandt, M.A.; Gu, J.; Lin, J.; Ye, Y.; Tan, W.; Tamboli, P.; Wood, C.G.; Wu, X. Hsa-miR-9 methylation status is associated with cancer development and metastatic recurrence in patients with clear cell renal cell carcinoma. Oncogene 2010, 29, 5724–5728. [Google Scholar] [CrossRef] [PubMed]
  126. Kohler, C.U.; Bryk, O.; Meier, S.; Lang, K.; Rozynek, P.; Bruning, T.; Kafferlein, H.U. Analyses in human urothelial cells identify methylation of miR-152, miR-200b and miR-10a genes as candidate bladder cancer biomarkers. Biochem. Biophys. Res. Commun. 2013, 438, 48–53. [Google Scholar] [CrossRef] [PubMed]
  127. Shen, J.; Wang, S.; Zhang, Y.J.; Kappil, M.A.; Wu, H.C.; Kibriya, M.G.; Wang, Q.; Jasmine, F.; Ahsan, H.; Lee, P.H.; et al. Genome-wide aberrant DNA methylation of microRNA host genes in hepatocellular carcinoma. Epigenetics 2012, 7, 1230–1237. [Google Scholar] [CrossRef] [PubMed]
  128. Humphreys, K.J.; Cobiac, L.; Le Leu, R.K.; Van der Hoek, M.B.; Michael, M.Z. Histone deacetylase inhibition in colorectal cancer cells reveals competing roles for members of the oncogenic miR-17-92 cluster. Mol. Carcinog. 2013, 52, 459–474. [Google Scholar] [CrossRef] [PubMed]
  129. Iorio, M.V.; Visone, R.; Di Leva, G.; Donati, V.; Petrocca, F.; Casalini, P.; Taccioli, C.; Volinia, S.; Liu, C.G.; Alder, H.; et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007, 67, 8699–8707. [Google Scholar] [CrossRef] [PubMed]
  130. Ferraro, A.; Kontos, C.K.; Boni, T.; Bantounas, I.; Siakouli, D.; Kosmidou, V.; Vlassi, M.; Spyridakis, Y.; Tsipras, I.; Zografos, G.; et al. Epigenetic regulation of miR-21 in colorectal cancer: ITGB4 as a novel miR-21 target and a three-gene network (miR-21-ITGBETA4-PDCD4) as predictor of metastatic tumor potential. Epigenetics 2014, 9, 129–141. [Google Scholar] [CrossRef] [PubMed]
  131. Hulf, T.; Sibbritt, T.; Wiklund, E.D.; Bert, S.; Strbenac, D.; Statham, A.L.; Robinson, M.D.; Clark, S.J. Discovery pipeline for epigenetically deregulated miRnas in cancer: Integration of primary miRNA transcription. BMC Genom. 2011, 12, 54. [Google Scholar] [CrossRef] [PubMed]
  132. Wang, S.; Zhang, R.; Claret, F.X.; Yang, H. Involvement of microRNA-24 and DNA methylation in resistance of nasopharyngeal carcinoma to ionizing radiation. Mol. Cancer Ther. 2014, 13, 3163–3174. [Google Scholar] [CrossRef] [PubMed]
  133. Zhang, X.; Zhao, X.; Fiskus, W.; Lin, J.; Lwin, T.; Rao, R.; Zhang, Y.; Chan, J.C.; Fu, K.; Marquez, V.E.; et al. Coordinated silencing of MYC-mediated miR-29 by HDAC3 AND EZH2 as a therapeutic target of histone modification in aggressive B-cell lymphomas. Cancer Cell 2012, 22, 506–523. [Google Scholar] [CrossRef] [PubMed]
  134. Liu, S.; Wu, L.C.; Pang, J.; Santhanam, R.; Schwind, S.; Wu, Y.Z.; Hickey, C.J.; Yu, J.; Becker, H.; Maharry, K.; et al. Sp1/NFκB/HDAC/miR-29b regulatory network in kit-driven myeloid leukemia. Cancer Cell 2010, 17, 333–347. [Google Scholar] [CrossRef] [PubMed]
  135. Cho, J.H.; Dimri, M.; Dimri, G.P. MicroRNA-31 is a transcriptional target of histone deacetylase inhibitors and a regulator of cellular senescence. J. Biol. Chem. 2015, 290, 10555–10567. [Google Scholar] [CrossRef] [PubMed]
  136. Lin, P.C.; Chiu, Y.L.; Banerjee, S.; Park, K.; Mosquera, J.M.; Giannopoulou, E.; Alves, P.; Tewari, A.K.; Gerstein, M.B.; Beltran, H.; et al. Epigenetic repression of miR-31 disrupts androgen receptor homeostasis and contributes to prostate cancer progression. Cancer Res. 2013, 73, 1232–1244. [Google Scholar] [CrossRef] [PubMed]
  137. Asangani, I.A.; Harms, P.W.; Dodson, L.; Pandhi, M.; Kunju, L.P.; Maher, C.A.; Fullen, D.R.; Johnson, T.M.; Giordano, T.J.; Palanisamy, N.; et al. Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma. Oncotarget 2012, 3, 1011–1025. [Google Scholar] [CrossRef] [PubMed]
  138. Augoff, K.; McCue, B.; Plow, E.F.; Sossey-Alaoui, K. miR-31 and its host gene lncRNA LOC554202 are regulated by promoter hypermethylation in triple-negative breast cancer. Mol. Cancer 2012, 11. [Google Scholar] [CrossRef] [PubMed]
  139. Bhatnagar, N.; Li, X.; Padi, S.K.; Zhang, Q.; Tang, M.S.; Guo, B. Downregulation of miR-205 and miR-31 confers resistance to chemotherapy-induced apoptosis in prostate cancer cells. Cell Death Dis. 2010, 1, e105. [Google Scholar] [CrossRef] [PubMed]
  140. Lodygin, D.; Tarasov, V.; Epanchintsev, A.; Berking, C.; Knyazeva, T.; Korner, H.; Knyazev, P.; Diebold, J.; Hermeking, H. Inactivation of miR-34a by aberrant cpg methylation in multiple types of cancer. Cell Cycle 2008, 7, 2591–2600. [Google Scholar] [CrossRef] [PubMed]
  141. Vogt, M.; Munding, J.; Gruner, M.; Liffers, S.T.; Verdoodt, B.; Hauk, J.; Steinstraesser, L.; Tannapfel, A.; Hermeking, H. Frequent concomitant inactivation of miR-34a and miR-34b/c by cpg methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas. Virchows Arch. 2011, 458, 313–322. [Google Scholar] [CrossRef] [PubMed]
  142. Kim, Y.H.; Lee, W.K.; Lee, E.B.; Son, J.W.; Kim, D.S.; Park, J.Y. Combined effect of metastasis-related microRNA, miR-34 and miR-124 family, methylation on prognosis of non-small-cell lung cancer. Clin. Lung Cancer 2017, 18, e13–e20. [Google Scholar] [CrossRef] [PubMed]
  143. Muraoka, T.; Soh, J.; Toyooka, S.; Aoe, K.; Fujimoto, N.; Hashida, S.; Maki, Y.; Tanaka, N.; Shien, K.; Furukawa, M.; et al. The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma. Lung Cancer 2013, 82, 485–490. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Parodi, F.; Carosio, R.; Ragusa, M.; Di Pietro, C.; Maugeri, M.; Barbagallo, D.; Sallustio, F.; Allemanni, G.; Pistillo, M.P.; Casciano, I.; et al. Epigenetic dysregulation in neuroblastoma: A tale of miRnas and DNA methylation. Biochim. Biophys. Acta 2016, 1859, 1502–1514. [Google Scholar] [CrossRef] [PubMed]
  145. Kozaki, K.; Imoto, I.; Mogi, S.; Omura, K.; Inazawa, J. Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res. 2008, 68, 2094–2105. [Google Scholar] [CrossRef] [PubMed]
  146. Lee, K.H.; Lotterman, C.; Karikari, C.; Omura, N.; Feldmann, G.; Habbe, N.; Goggins, M.G.; Mendell, J.T.; Maitra, A. Epigenetic silencing of microRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer. Pancreatology 2009, 9, 293–301. [Google Scholar] [CrossRef] [PubMed]
  147. Chu, M.; Chang, Y.; Guo, Y.; Wang, N.; Cui, J.; Gao, W.Q. Regulation and methylation of tumor suppressor miR-124 by androgen receptor in prostate cancer cells. PLoS ONE 2015, 10, e0116197. [Google Scholar] [CrossRef] [PubMed]
  148. Agirre, X.; Vilas-Zornoza, A.; Jimenez-Velasco, A.; Martin-Subero, J.I.; Cordeu, L.; Garate, L.; San Jose-Eneriz, E.; Abizanda, G.; Rodriguez-Otero, P.; Fortes, P.; et al. Epigenetic silencing of the tumor suppressor microRNA hsa-miR-124a regulates CDK6 expression and confers a poor prognosis in acute lymphoblastic leukemia. Cancer Res. 2009, 69, 4443–4453. [Google Scholar] [CrossRef] [PubMed]
  149. Gebauer, K.; Peters, I.; Dubrowinskaja, N.; Hennenlotter, J.; Abbas, M.; Scherer, R.; Tezval, H.; Merseburger, A.S.; Stenzl, A.; Kuczyk, M.A.; et al. Hsa-miR-124-3 CPG island methylation is associated with advanced tumours and disease recurrence of patients with clear cell renal cell carcinoma. Br. J. Cancer 2013, 108, 131–138. [Google Scholar] [CrossRef] [PubMed]
  150. Wilting, S.M.; van Boerdonk, R.A.; Henken, F.E.; Meijer, C.J.; Diosdado, B.; Meijer, G.A.; le Sage, C.; Agami, R.; Snijders, P.J.; Steenbergen, R.D. Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer. Mol. Cancer 2010, 9, 167. [Google Scholar] [CrossRef] [PubMed]
  151. Silber, J.; Lim, D.A.; Petritsch, C.; Persson, A.I.; Maunakea, A.K.; Yu, M.; Vandenberg, S.R.; Ginzinger, D.G.; James, C.D.; Costello, J.F.; et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008, 6, 14. [Google Scholar] [CrossRef] [PubMed]
  152. Deng, G.; Kakar, S.; Kim, Y.S. MicroRNA-124a and microRNA-34b/c are frequently methylated in all histological types of colorectal cancer and polyps, and in the adjacent normal mucosa. Oncol. Lett. 2011, 2, 175–180. [Google Scholar] [CrossRef] [PubMed]
  153. Alpini, G.; Glaser, S.S.; Zhang, J.P.; Francis, H.; Han, Y.; Gong, J.; Stokes, A.; Francis, T.; Hughart, N.; Hubble, L.; et al. Regulation of placenta growth factor by microRNA-125b in hepatocellular cancer. J. Hepatol. 2011, 55, 1339–1345. [Google Scholar] [CrossRef] [PubMed]
  154. Andersen, M.; Trapani, D.; Ravn, J.; Sorensen, J.B.; Andersen, C.B.; Grauslund, M.; Santoni-Rugiu, E. Methylation-associated silencing of microRNA-126 and its host gene EGFl7 in malignant pleural mesothelioma. Anticancer Res. 2015, 35, 6223–6229. [Google Scholar] [PubMed]
  155. Zhang, Y.; Wang, X.; Xu, B.; Wang, B.; Wang, Z.; Liang, Y.; Zhou, J.; Hu, J.; Jiang, B. Epigenetic silencing of miR-126 contributes to tumor invasion and angiogenesis in colorectal cancer. Oncol. Rep. 2013, 30, 1976–1984. [Google Scholar] [CrossRef] [PubMed]
  156. Saito, Y.; Friedman, J.M.; Chihara, Y.; Egger, G.; Chuang, J.C.; Liang, G. Epigenetic therapy upregulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells. Biochem. Biophys. Res. Commun. 2009, 379, 726–731. [Google Scholar] [CrossRef] [PubMed]
  157. Watanabe, K.; Emoto, N.; Hamano, E.; Sunohara, M.; Kawakami, M.; Kage, H.; Kitano, K.; Nakajima, J.; Goto, A.; Fukayama, M.; et al. Genome structure-based screening identified epigenetically silenced microRNA associated with invasiveness in non-small-cell lung cancer. Int. J. Cancer 2012, 130, 2580–2590. [Google Scholar] [CrossRef] [PubMed]
  158. Wotschofsky, Z.; Liep, J.; Meyer, H.A.; Jung, M.; Wagner, I.; Disch, A.C.; Schaser, K.D.; Melcher, I.; Kilic, E.; Busch, J.; et al. Identification of metastamiRs as metastasis-associated microRNAs in clear cell renal cell carcinomas. Int. J. Biol. Sci. 2012, 8, 1363–1374. [Google Scholar] [CrossRef] [PubMed]
  159. Chen, X.; Zhang, L.; Zhang, T.; Hao, M.; Zhang, X.; Zhang, J.; Xie, Q.; Wang, Y.; Guo, M.; Zhuang, H.; et al. Methylation-mediated repression of microRNA 129-2 enhances oncogenic SOX4 expression in HCC. Liver Int. 2013, 33, 476–486. [Google Scholar] [CrossRef] [PubMed]
  160. Huang, Y.W.; Liu, J.C.; Deatherage, D.E.; Luo, J.; Mutch, D.G.; Goodfellow, P.J.; Miller, D.S.; Huang, T.H. Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer. Cancer Res. 2009, 69, 9038–9046. [Google Scholar] [CrossRef] [PubMed]
  161. Shen, R.; Pan, S.; Qi, S.; Lin, X.; Cheng, S. Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 in gastric cancer. Biochem. Biophys. Res. Commun. 2010, 394, 1047–1052. [Google Scholar] [CrossRef] [PubMed]
  162. Wong, K.Y.; Yim, R.L.; Kwong, Y.L.; Leung, C.Y.; Hui, P.K.; Cheung, F.; Liang, R.; Jin, D.Y.; Chim, C.S. Epigenetic inactivation of the miR129-2 in hematological malignancies. J. Hematol. Oncol. 2013, 6, 16. [Google Scholar] [CrossRef] [PubMed]
  163. Bandres, E.; Agirre, X.; Bitarte, N.; RamiRez, N.; Zarate, R.; Roman-Gomez, J.; Prosper, F.; Garcia-Foncillas, J. Epigenetic regulation of microRNA expression in colorectal cancer. Int. J. Cancer 2009, 125, 2737–2743. [Google Scholar] [CrossRef] [PubMed]
  164. Zhang, S.; Hao, J.; Xie, F.; Hu, X.; Liu, C.; Tong, J.; Zhou, J.; Wu, J.; Shao, C. Downregulation of miR-132 by promoter methylation contributes to pancreatic cancer development. Carcinogenesis 2011, 32, 1183–1189. [Google Scholar] [CrossRef] [PubMed]
  165. Formosa, A.; Lena, A.M.; Markert, E.K.; Cortelli, S.; Miano, R.; Mauriello, A.; Croce, N.; Vandesompele, J.; Mestdagh, P.; Finazzi-Agro, E.; et al. DNA methylation silences miR-132 in prostate cancer. Oncogene 2013, 32, 127–134. [Google Scholar] [CrossRef] [PubMed]
  166. Lv, L.V.; Zhou, J.; Lin, C.; Hu, G.; Yi, L.U.; Du, J.; Gao, K.; Li, X. DNA methylation is involved in the aberrant expression of miR-133b in colorectal cancer cells. Oncol. Lett. 2015, 10, 907–912. [Google Scholar] [CrossRef] [PubMed]
  167. Qin, Y.; Zhang, S.; Deng, S.; An, G.; Qin, X.; Li, F.; Xu, Y.; Hao, M.; Yang, Y.; Zhou, W.; et al. Epigenetic silencing of miR-137 induces drug resistance and chromosomal instability by targeting AURKA in multiple myeloma. Leukemia 2017, 31, 1123–1135. [Google Scholar] [CrossRef] [PubMed]
  168. Langevin, S.M.; Stone, R.A.; Bunker, C.H.; Lyons-Weiler, M.A.; LaFramboise, W.A.; Kelly, L.; Seethala, R.R.; Grandis, J.R.; Sobol, R.W.; Taioli, E. MicroRNA-137 promoter methylation is associated with poorer overall survival in patients with squamous cell carcinoma of the head and neck. Cancer 2011, 117, 1454–1462. [Google Scholar] [CrossRef] [PubMed]
  169. Steponaitiene, R.; Kupcinskas, J.; Langner, C.; Balaguer, F.; Venclauskas, L.; Pauzas, H.; Tamelis, A.; Skieceviciene, J.; Kupcinskas, L.; Malfertheiner, P.; et al. Epigenetic silencing of miR-137 is a frequent event in gastric carcinogenesis. Mol. Carcinog. 2016, 55, 376–386. [Google Scholar] [CrossRef] [PubMed]
  170. Balaguer, F.; Link, A.; Lozano, J.J.; Cuatrecasas, M.; Nagasaka, T.; Boland, C.R.; Goel, A. Epigenetic silencing of miR-137 is an early event in colorectal carcinogenesis. Cancer Res. 2010, 70, 6609–6618. [Google Scholar] [CrossRef] [PubMed]
  171. Daniunaite, K.; Dubikaityte, M.; Gibas, P.; Bakavicius, A.; Rimantas Lazutka, J.; Ulys, A.; Jankevicius, F.; Jarmalaite, S. Clinical significance of miRna host gene promoter methylation in prostate cancer. Hum. Mol. Genet. 2017, 26, 2451–2461. [Google Scholar] [CrossRef] [PubMed]
  172. Watanabe, K.; Amano, Y.; Ishikawa, R.; Sunohara, M.; Kage, H.; Ichinose, J.; Sano, A.; Nakajima, J.; Fukayama, M.; Yatomi, Y.; et al. Histone methylation-mediated silencing of miR-139 enhances invasion of non-small-cell lung cancer. Cancer Med. 2015, 4, 1573–1582. [Google Scholar] [CrossRef] [PubMed]
  173. Wong, C.C.; Wong, C.M.; Tung, E.K.; Au, S.L.; Lee, J.M.; Poon, R.T.; Man, K.; Ng, I.O. The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2. Gastroenterology 2011, 140, 322–331. [Google Scholar] [CrossRef] [PubMed]
  174. Lynch, S.M.; O'Neill, K.M.; McKenna, M.M.; Walsh, C.P.; McKenna, D.J. Regulation of miR-200c and miR-141 by methylation in prostate cancer. Prostate 2016, 76, 1146–1159. [Google Scholar] [CrossRef] [PubMed]
  175. Dou, L.; Zheng, D.; Li, J.; Li, Y.; Gao, L.; Wang, L.; Yu, L. Methylation-mediated repression of microRNA-143 enhances MLL-AF4 oncogene expression. Oncogene 2012, 31, 507–517. [Google Scholar] [CrossRef] [PubMed]
  176. Xia, W.; Chen, Q.; Wang, J.; Mao, Q.; Dong, G.; Shi, R.; Zheng, Y.; Xu, L.; Jiang, F. DNA methylation mediated silencing of microRNA-145 is a potential prognostic marker in patients with lung adenocarcinoma. Sci. Rep. 2015, 5, 16901. [Google Scholar] [CrossRef] [PubMed]
  177. Ye, Z.; Shen, N.; Weng, Y.; Li, K.; Hu, L.; Liao, H.; An, J.; Liu, L.; Lao, S.; Cai, S. Low miR-145 silenced by DNA methylation promotes NSCLC cell proliferation, migration and invasion by targeting mucin 1. Cancer Biol. Ther. 2015, 16, 1071–1079. [Google Scholar] [CrossRef] [PubMed]
  178. Suh, S.O.; Chen, Y.; Zaman, M.S.; Hirata, H.; Yamamura, S.; Shahryari, V.; Liu, J.; Tabatabai, Z.L.; Kakar, S.; Deng, G.; et al. MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer. Carcinogenesis 2011, 32, 772–778. [Google Scholar] [CrossRef] [PubMed]
  179. Zaman, M.S.; Chen, Y.; Deng, G.; Shahryari, V.; Suh, S.O.; Saini, S.; Majid, S.; Liu, J.; Khatri, G.; Tanaka, Y.; et al. The functional significance of microRNA-145 in prostate cancer. Br. J. Cancer 2010, 103, 256–264. [Google Scholar] [CrossRef] [PubMed]
  180. Tsuruta, T.; Kozaki, K.; Uesugi, A.; Furuta, M.; Hirasawa, A.; Imoto, I.; Susumu, N.; Aoki, D.; Inazawa, J. miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer. Cancer Res. 2011, 71, 6450–6462. [Google Scholar] [CrossRef] [PubMed]
  181. Sengupta, D.; Deb, M.; Rath, S.K.; Kar, S.; Parbin, S.; Pradhan, N.; Patra, S.K. DNA methylation and not H3K4 trimethylation dictates the expression status of miR-152 gene which inhibits migration of breast cancer cells via DNMT1/CDH1 loop. Exp. Cell Res. 2016, 346, 176–187. [Google Scholar] [CrossRef] [PubMed]
  182. Ayala-Ortega, E.; Arzate-Mejia, R.; Perez-Molina, R.; Gonzalez-Buendia, E.; Meier, K.; Guerrero, G.; Recillas-Targa, F. Epigenetic silencing of miR-181c by DNA methylation in glioblastoma cell lines. BMC Cancer 2016, 16, 226. [Google Scholar] [CrossRef] [PubMed]
  183. He, Y.; Cui, Y.; Wang, W.; Gu, J.; Guo, S.; Ma, K.; Luo, X. Hypomethylation of the hsa-miR-191 locus causes high expression of hsa-miR-191 and promotes the epithelial-to-mesenchymal transition in hepatocellular carcinoma. Neoplasia 2011, 13, 841–853. [Google Scholar] [CrossRef] [PubMed]
  184. Ma, K.; He, Y.; Zhang, H.; Fei, Q.; Niu, D.; Wang, D.; Ding, X.; Xu, H.; Chen, X.; Zhu, J. DNA methylation-regulated miR-193a-3p dictates resistance of hepatocellular carcinoma to 5-fluorouracil via repression of SRSF2 expression. J. Biol. Chem. 2012, 287, 5639–5649. [Google Scholar] [CrossRef] [PubMed]
  185. Lv, L.; Deng, H.; Li, Y.; Zhang, C.; Liu, X.; Liu, Q.; Zhang, D.; Wang, L.; Pu, Y.; Zhang, H.; et al. The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression. Cell Death Dis. 2014, 5, e1402. [Google Scholar] [CrossRef] [PubMed]
  186. Gao, X.N.; Lin, J.; Li, Y.H.; Gao, L.; Wang, X.R.; Wang, W.; Kang, H.Y.; Yan, G.T.; Wang, L.L.; Yu, L. MicroRNA-193a represses c-kit expression and functions as a methylation-silenced tumor suppressor in acute myeloid leukemia. Oncogene 2011, 30, 3416–3428. [Google Scholar] [CrossRef] [PubMed]
  187. Torres-Ferreira, J.; Ramalho-Carvalho, J.; Gomez, A.; Menezes, F.D.; Freitas, R.; Oliveira, J.; Antunes, L.; Bento, M.J.; Esteller, M.; Henrique, R.; et al. miR-193b promoter methylation accurately detects prostate cancer in urine sediments and miR-34b/c or miR-129-2 promoter methylation define subsets of clinically aggressive tumors. Mol. Cancer 2017, 16, 26. [Google Scholar] [CrossRef] [PubMed]
  188. Rauhala, H.E.; Jalava, S.E.; Isotalo, J.; Bracken, H.; Lehmusvaara, S.; Tammela, T.L.; Oja, H.; Visakorpi, T. miR-193b is an epigenetically regulated putative tumor suppressor in prostate cancer. Int. J. Cancer 2010, 127, 1363–1372. [Google Scholar] [CrossRef] [PubMed]
  189. Tsai, K.W.; Hu, L.Y.; Wu, C.W.; Li, S.C.; Lai, C.H.; Kao, H.W.; Fang, W.L.; Lin, W.C. Epigenetic regulation of miR-196b expression in gastric cancer. Genes Chromosom. Cancer 2010, 49, 969–980. [Google Scholar] [CrossRef] [PubMed]
  190. Cheung, H.H.; Davis, A.J.; Lee, T.L.; Pang, A.L.; Nagrani, S.; Rennert, O.M.; Chan, W.Y. Methylation of an intronic region regulates miR-199a in testicular tumor malignancy. Oncogene 2011, 30, 3404–3415. [Google Scholar] [CrossRef] [PubMed]
  191. Deng, Y.; Zhao, F.; Hui, L.; Li, X.; Zhang, D.; Lin, W.; Chen, Z.; Ning, Y. Suppressing miR-199a-3p by promoter methylation contributes to tumor aggressiveness and cisplatin resistance of ovarian cancer through promoting DDR1 expression. J. Ovarian Res. 2017, 10, 50. [Google Scholar] [CrossRef] [PubMed]
  192. Wu, W.R.; Sun, H.; Zhang, R.; Yu, X.H.; Shi, X.D.; Zhu, M.S.; Zeng, H.; Yan, L.X.; Xu, L.B.; Liu, C. Methylation-associated silencing of miR-200b facilitates human hepatocellular carcinoma progression by directly targeting BMI1. Oncotarget 2016, 7, 18684–18693. [Google Scholar] [CrossRef] [PubMed]
  193. Neves, R.; Scheel, C.; Weinhold, S.; Honisch, E.; Iwaniuk, K.M.; Trompeter, H.I.; Niederacher, D.; Wernet, P.; Santourlidis, S.; Uhrberg, M. Role of DNA methylation in miR-200c/141 cluster silencing in invasive breast cancer cells. BMC Res. Notes 2010, 3, 219. [Google Scholar] [CrossRef] [PubMed]
  194. Ceppi, P.; Mudduluru, G.; Kumarswamy, R.; Rapa, I.; Scagliotti, G.V.; Papotti, M.; Allgayer, H. Loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer. Mol. Cancer Res. MCR 2010, 8, 1207–1216. [Google Scholar] [CrossRef] [PubMed]
  195. Davalos, V.; Moutinho, C.; Villanueva, A.; Boque, R.; Silva, P.; Carneiro, F.; Esteller, M. Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis. Oncogene 2012, 31, 2062–2074. [Google Scholar] [CrossRef] [PubMed]
  196. Huang, Y.W.; Kuo, C.T.; Chen, J.H.; Goodfellow, P.J.; Huang, T.H.; Rader, J.S.; Uyar, D.S. Hypermethylation of miR-203 in endometrial carcinomas. Gynecol. Oncol. 2014, 133, 340–345. [Google Scholar] [CrossRef] [PubMed]
  197. Chim, C.S.; Wong, K.Y.; Leung, C.Y.; Chung, L.P.; Hui, P.K.; Chan, S.Y.; Yu, L. Epigenetic inactivation of the hsa-miR-203 in haematological malignancies. J. Cell Mol. Med. 2011, 15, 2760–2767. [Google Scholar] [CrossRef] [PubMed]
  198. Wiklund, E.D.; Bramsen, J.B.; Hulf, T.; Dyrskjot, L.; Ramanathan, R.; Hansen, T.B.; Villadsen, S.B.; Gao, S.; Ostenfeld, M.S.; Borre, M.; et al. Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int. J. Cancer 2011, 128, 1327–1334. [Google Scholar] [CrossRef] [PubMed]
  199. Uesugi, A.; Kozaki, K.; Tsuruta, T.; Furuta, M.; Morita, K.; Imoto, I.; Omura, K.; Inazawa, J. The tumor suppressive microRNA miR-218 targets the mtor component rictor and inhibits AKT phosphorylation in oral cancer. Cancer Res. 2011, 71, 5765–5778. [Google Scholar] [CrossRef] [PubMed]
  200. Lei, H.; Zou, D.; Li, Z.; Luo, M.; Dong, L.; Wang, B.; Yin, H.; Ma, Y.; Liu, C.; Wang, F.; et al. MicroRNA-219-2-3p functions as a tumor suppressor in gastric cancer and is regulated by DNA methylation. PLoS ONE 2013, 8, e60369. [Google Scholar] [CrossRef] [PubMed]
  201. Png, K.J.; Yoshida, M.; Zhang, X.H.; Shu, W.; Lee, H.; Rimner, A.; Chan, T.A.; Comen, E.; Andrade, V.P.; Kim, S.W.; et al. MicroRNA-335 inhibits tumor reinitiation and is silenced through genetic and epigenetic mechanisms in human breast cancer. Genes Dev. 2011, 25, 226–231. [Google Scholar] [CrossRef] [PubMed]
  202. Li, Z.; Li, D.; Zhang, G.; Xiong, J.; Jie, Z.; Cheng, H.; Cao, Y.; Jiang, M.; Lin, L.; Le, Z.; et al. Methylation-associated silencing of microRNA-335 contributes tumor cell invasion and migration by interacting with rasa1 in gastric cancer. Am. J. Cancer Res. 2014, 4, 648–662. [Google Scholar] [PubMed]
  203. Dohi, O.; Yasui, K.; Gen, Y.; Takada, H.; Endo, M.; Tsuji, K.; Konishi, C.; Yamada, N.; Mitsuyoshi, H.; Yagi, N.; et al. Epigenetic silencing of miR-335 and its host gene mest in hepatocellular carcinoma. Int. J. Oncol. 2013, 42, 411–418. [Google Scholar] [CrossRef] [PubMed]
  204. Zhang, J.K.; Li, Y.S.; Zhang, C.D.; Dai, D.Q. Up-regulation of crkl by microRNA-335 methylation is associated with poor prognosis in gastric cancer. Cancer Cell Int. 2017, 17, 28. [Google Scholar] [CrossRef] [PubMed]
  205. Grady, W.M.; Parkin, R.K.; Mitchell, P.S.; Lee, J.H.; Kim, Y.H.; Tsuchiya, K.D.; Washington, M.K.; Paraskeva, C.; Willson, J.K.; Kaz, A.M.; et al. Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene evl in colorectal cancer. Oncogene 2008, 27, 3880–3888. [Google Scholar] [CrossRef] [PubMed]
  206. Tang, J.T.; Wang, J.L.; Du, W.; Hong, J.; Zhao, S.L.; Wang, Y.C.; Xiong, H.; Chen, H.M.; Fang, J.Y. MicroRNA 345, a methylation-sensitive microRNA is involved in cell proliferation and invasion in human colorectal cancer. Carcinogenesis 2011, 32, 1207–1215. [Google Scholar] [CrossRef] [PubMed]
  207. Nakaoka, T.; Saito, Y.; Saito, H. Aberrant DNA methylation as a biomarker and a therapeutic target of cholangiocarcinoma. Int. J. Mol. Sci. 2017, 18, 1111. [Google Scholar] [CrossRef] [PubMed]
  208. Chang, K.W.; Chu, T.H.; Gong, N.R.; Chiang, W.F.; Yang, C.C.; Liu, C.J.; Wu, C.H.; Lin, S.C. miR-370 modulates insulin receptor substrate-1 expression and inhibits the tumor phenotypes of oral carcinoma. Oral Dis. 2013, 19, 611–619. [Google Scholar] [CrossRef] [PubMed]
  209. Chen, Y.; Gao, W.; Luo, J.; Tian, R.; Sun, H.; Zou, S. Methyl-CpG binding protein MBD2 is implicated in methylation-mediated suppression of miR-373 in hilar cholangiocarcinoma. Oncol. Rep. 2011, 25, 443–451. [Google Scholar] [CrossRef] [PubMed]
  210. Chu, M.; Chang, Y.; Li, P.; Guo, Y.; Zhang, K.; Gao, W. Androgen receptor is negatively correlated with the methylation-mediated transcriptional repression of miR-375 in human prostate cancer cells. Oncol. Rep. 2014, 31, 34–40. [Google Scholar] [CrossRef] [PubMed]
  211. Li, X.; Lin, R.; Li, J. Epigenetic silencing of microRNA-375 regulates pdk1 expression in esophageal cancer. Dig. Dis. Sci. 2011, 56, 2849–2856. [Google Scholar] [CrossRef] [PubMed]
  212. Mazar, J.; DeBlasio, D.; Govindarajan, S.S.; Zhang, S.; Perera, R.J. Epigenetic regulation of microRNA-375 and its role in melanoma development in humans. FEBS Lett. 2011, 585, 2467–2476. [Google Scholar] [CrossRef] [PubMed]
  213. Zhang, L.; Yan, D.L.; Yang, F.; Wang, D.D.; Chen, X.; Wu, J.Z.; Tang, J.H.; Xia, W.J. DNA methylation mediated silencing of microRNA-874 is a promising diagnosis and prognostic marker in breast cancer. Oncotarget 2017, 8, 45496–45505. [Google Scholar] [CrossRef] [PubMed]
  214. Yan, H.; Choi, A.J.; Lee, B.H.; Ting, A.H. Identification and functional analysis of epigenetically silenced microRNAs in colorectal cancer cells. PLoS ONE 2011, 6, e20628. [Google Scholar] [CrossRef] [PubMed]
  215. Kim, J.G.; Kim, T.O.; Bae, J.H.; Shim, J.W.; Kang, M.J.; Yang, K.; Ting, A.H.; Yi, J.M. Epigenetically regulated MIR941 and MIR1247 target gastric cancer cell growth and migration. Epigenetics 2014, 9, 1018–1030. [Google Scholar] [CrossRef] [PubMed]
  216. Dudziec, E.; Miah, S.; Choudhry, H.M.; Owen, H.C.; Blizard, S.; Glover, M.; Hamdy, F.C.; Catto, J.W. Hypermethylation of CpG islands and shores around specific microRNAs and miRtrons is associated with the phenotype and presence of bladder cancer. Clin. Cancer Res. 2011, 17, 1287–1296. [Google Scholar] [CrossRef] [PubMed]
  217. Zhang, X.; Liu, H.; Xie, Z.; Deng, W.; Wu, C.; Qin, B.; Hou, J.; Lu, M. Epigenetically regulated miR-449a enhances hepatitis b virus replication by targeting cAMP-responsive element binding protein 5 and modulating hepatocytes phenotype. Sci. Rep. 2016, 6, 25389. [Google Scholar] [CrossRef] [PubMed]
  218. Ko, Y.C.; Fang, W.H.; Lin, T.C.; Hou, H.A.; Chen, C.Y.; Tien, H.F.; Lin, L.I. MicroRNA let-7a-3 gene methylation is associated with karyotyping, CEBPA promoter methylation, and survival in acute myeloid leukemia. Leuk. Res. 2014, 38, 625–631. [Google Scholar] [CrossRef] [PubMed]
  219. Lu, L.; Katsaros, D.; de la Longrais, I.A.; Sochirca, O.; Yu, H. Hypermethylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis. Cancer Res. 2007, 67, 10117–10122. [Google Scholar] [CrossRef] [PubMed]
  220. Brueckner, B.; Stresemann, C.; Kuner, R.; Mund, C.; Musch, T.; Meister, M.; Sultmann, H.; Lyko, F. The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res. 2007, 67, 1419–1423. [Google Scholar] [CrossRef] [PubMed]
  221. Wong, T.S.; Man, O.Y.; Tsang, C.M.; Tsao, S.W.; Tsang, R.K.; Chan, J.Y.; Ho, W.K.; Wei, W.I.; To, V.S. MicroRNA let-7 suppresses nasopharyngeal carcinoma cells proliferation through downregulating c-Myc expression. J. Cancer Res. Clin. Oncol. 2011, 137, 415–422. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  222. Geeleher, P.; Huang, S.R.; Gamazon, E.R.; Golden, A.; Seoighe, C. The regulatory effect of miRNAs is a heritable genetic trait in humans. BMC Genom. 2012, 13, 383. [Google Scholar]
  223. Lim, J.P.; Brunet, A. Bridging the transgenerational gap with epigenetic memory. Trends Genet. 2013, 29, 176–186. [Google Scholar] [CrossRef] [PubMed]
  224. Liebers, R.; Rassoulzadegan, M.; Lyko, F. Epigenetic regulation by heritable RNA. PLoS Genet. 2014, 10, e1004296. [Google Scholar] [CrossRef] [PubMed]
  225. Goldberg, A.D.; Allis, C.D.; Bernstein, E. Epigenetics: A landscape takes shape. Cell 2007, 128, 635–638. [Google Scholar] [CrossRef] [PubMed]
  226. Kazanets, A.; Shorstova, T.; Hilmi, K.; Marques, M.; Witcher, M. Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential. Biochim. Biophys. Acta 2016, 1865, 275–288. [Google Scholar] [PubMed]
  227. Zhang, W.; Xu, J. DNA methyltransferases and their roles in tumorigenesis. Biomark. Res. 2017, 5. [Google Scholar] [CrossRef] [PubMed]
  228. Braconi, C.; Kogure, T.; Valeri, N.; Huang, N.; Nuovo, G.; Costinean, S.; Negrini, M.; Miotto, E.; Croce, C.M.; Patel, T. MicroRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene 2011, 30, 4750–4756. [Google Scholar] [CrossRef] [PubMed]
  229. Duursma, A.M.; Kedde, M.; Schrier, M.; le Sage, C.; Agami, R. miR-148 targets human DNMT3b protein coding region. RNA 2008, 14, 872–877. [Google Scholar] [CrossRef] [PubMed]
  230. Benetti, R.; Gonzalo, S.; Jaco, I.; Munoz, P.; Gonzalez, S.; Schoeftner, S.; Murchison, E.; Andl, T.; Chen, T.; Klatt, P.; et al. A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nat. Struct. Mol. Biol. 2008, 15, 998. [Google Scholar] [CrossRef] [PubMed]
  231. Vire, E.; Brenner, C.; Deplus, R.; Blanchon, L.; Fraga, M.; Didelot, C.; Morey, L.; Van Eynde, A.; Bernard, D.; Vanderwinden, J.M.; et al. The polycomb group protein EZH2 directly controls DNA methylation. Nature 2006, 439, 871–874. [Google Scholar] [CrossRef] [PubMed]
  232. Cao, R.; Wang, L.; Wang, H.; Xia, L.; Erdjument-Bromage, H.; Tempst, P.; Jones, R.S.; Zhang, Y. Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science 2002, 298, 1039–1043. [Google Scholar] [CrossRef] [PubMed]
  233. Cao, R.; Zhang, Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol. Cell 2004, 15, 57–67. [Google Scholar] [CrossRef] [PubMed]
  234. Iliopoulos, D.; Lindahl-Allen, M.; Polytarchou, C.; Hirsch, H.A.; Tsichlis, P.N.; Struhl, K. Loss of miR-200 inhibition of SUZ12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol. Cell 2010, 39, 761–772. [Google Scholar] [CrossRef] [PubMed]
  235. Peruzzi, P.; Bronisz, A.; Nowicki, M.O.; Wang, Y.; Ogawa, D.; Price, R.; Nakano, I.; Kwon, C.H.; Hayes, J.; Lawler, S.E.; et al. MicroRNA-128 coordinately targets polycomb repressor complexes in glioma stem cells. Neuro Oncol. 2013, 15, 1212–1224. [Google Scholar] [CrossRef] [PubMed]
  236. Kleer, C.G.; Cao, Q.; Varambally, S.; Shen, R.; Ota, I.; Tomlins, S.A.; Ghosh, D.; Sewalt, R.G.; Otte, A.P.; Hayes, D.F.; et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl. Acad. Sci. USA 2003, 100, 11606–11611. [Google Scholar] [CrossRef] [PubMed]
  237. Bachmann, I.M.; Halvorsen, O.J.; Collett, K.; Stefansson, I.M.; Straume, O.; Haukaas, S.A.; Salvesen, H.B.; Otte, A.P.; Akslen, L.A. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J. Clin. Oncol. 2006, 24, 268–273. [Google Scholar] [CrossRef] [PubMed]
  238. Sander, S.; Bullinger, L.; Klapproth, K.; Fiedler, K.; Kestler, H.A.; Barth, T.F.; Moller, P.; Stilgenbauer, S.; Pollack, J.R.; Wirth, T. MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood 2008, 112, 4202–4212. [Google Scholar] [CrossRef] [PubMed]
  239. Friedman, J.M.; Liang, G.; Liu, C.C.; Wolff, E.M.; Tsai, Y.C.; Ye, W.; Zhou, X.; Jones, P.A. The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer Res. 2009, 69, 2623–2629. [Google Scholar] [CrossRef] [PubMed]
  240. Varambally, S.; Cao, Q.; Mani, R.S.; Shankar, S.; Wang, X.; Ateeq, B.; Laxman, B.; Cao, X.; Jing, X.; Ramnarayanan, K.; et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 2008, 322, 1695–1699. [Google Scholar] [CrossRef] [PubMed]
  241. Di Croce, L.; Helin, K. Transcriptional regulation by polycomb group proteins. Nat. Struct. Mol. Biol. 2013, 20, 1147–1155. [Google Scholar] [CrossRef] [PubMed]
  242. Jiang, L.; Li, J.; Song, L. Bmi-1, stem cells and cancer. Acta Biochim. Biophys. Sin. (Shanghai) 2009, 41, 527–534. [Google Scholar] [CrossRef] [PubMed]
  243. Godlewski, J.; Nowicki, M.O.; Bronisz, A.; Williams, S.; Otsuki, A.; Nuovo, G.; Raychaudhury, A.; Newton, H.B.; Chiocca, E.A.; Lawler, S. Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res. 2008, 68, 9125–9130. [Google Scholar] [CrossRef] [PubMed]
  244. Bhattacharya, R.; Nicoloso, M.; Arvizo, R.; Wang, E.; Cortez, A.; Rossi, S.; Calin, G.A.; Mukherjee, P. miR-15a and miR-16 control Bmi-1 expression in ovarian cancer. Cancer Res. 2009, 69, 9090–9095. [Google Scholar] [CrossRef] [PubMed]
  245. Dong, P.; Kaneuchi, M.; Watari, H.; Hamada, J.; Sudo, S.; Ju, J.; Sakuragi, N. MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1. Mol. Cancer 2011, 10, 10–1186. [Google Scholar] [CrossRef] [PubMed]
  246. Tu, Y.; Gao, X.; Li, G.; Fu, H.; Cui, D.; Liu, H.; Jin, W.; Zhang, Y. MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1. Cancer Res. 2013, 73, 6046–6055. [Google Scholar] [CrossRef] [PubMed]
  247. Wu, S.Q.; Niu, W.Y.; Li, Y.P.; Huang, H.B.; Zhan, R. miR-203 inhibits cell growth and regulates G1/S transition by targeting Bmi-1 in myeloma cells. Mol. Med. Rep. 2016, 14, 4795–4801. [Google Scholar] [CrossRef] [PubMed]
  248. Van der Vlag, J.; Otte, A.P. Transcriptional repression mediated by the human polycomb-group protein eed involves histone deacetylation. Nat. Genet. 1999, 23, 474–478. [Google Scholar] [CrossRef] [PubMed]
  249. Witt, O.; Deubzer, H.E.; Milde, T.; Oehme, I. Hdac family: What are the cancer relevant targets? Cancer Lett. 2009, 277, 8–21. [Google Scholar] [CrossRef] [PubMed]
  250. Noonan, E.J.; Place, R.F.; Pookot, D.; Basak, S.; Whitson, J.M.; Hirata, H.; Giardina, C.; Dahiya, R. miR-449a targets HDAC-1 and induces growth arrest in prostate cancer. Oncogene 2009, 28, 1714–1724. [Google Scholar] [CrossRef] [PubMed]
  251. Noh, J.H.; Chang, Y.G.; Kim, M.G.; Jung, K.H.; Kim, J.K.; Bae, H.J.; Eun, J.W.; Shen, Q.; Kim, S.J.; Kwon, S.H.; et al. miR-145 functions as a tumor suppressor by directly targeting histone deacetylase 2 in liver cancer. Cancer Lett. 2013, 335, 455–462. [Google Scholar] [CrossRef] [PubMed]
  252. Sandhu, S.K.; Volinia, S.; Costinean, S.; Galasso, M.; Neinast, R.; Santhanam, R.; Parthun, M.R.; Perrotti, D.; Marcucci, G.; Garzon, R.; et al. miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eμ-miR-155 transgenic mouse model. Proc. Natl. Acad. Sci. USA 2012, 109, 20047–20052. [Google Scholar] [CrossRef] [PubMed]
  253. Canzio, D.; Larson, A.; Narlikar, G.J. Mechanisms of functional promiscuity by HP1 proteins. Trends Cell Biol. 2014, 24, 377–386. [Google Scholar] [CrossRef] [PubMed]
  254. Dialynas, G.K.; Vitalini, M.W.; Wallrath, L.L. Linking heterochromatin protein 1 (HP1) to cancer progression. Mutat. Res. 2008, 647, 13–20. [Google Scholar] [CrossRef] [PubMed]
  255. Liu, M.; Huang, F.; Zhang, D.; Ju, J.; Wu, X.B.; Wang, Y.; Wu, Y.; Nie, M.; Li, Z.; Ma, C.; et al. Heterochromatin protein HP1γ promotes colorectal cancer progression and is regulated by miR-30a. Cancer Res. 2015, 75, 4593–4604. [Google Scholar] [CrossRef] [PubMed]
  256. Zhang, H.; Yan, T.; Liu, Z.; Wang, J.; Lu, Y.; Li, D.; Liang, W. MicroRNA-137 is negatively associated with clinical outcome and regulates tumor development through EZH2 in cervical cancer. J. Cell Biochem. 2018, 119, 938–947. [Google Scholar] [CrossRef] [PubMed]
  257. Takata, A.; Otsuka, M.; Yoshikawa, T.; Kishikawa, T.; Hikiba, Y.; Obi, S.; Goto, T.; Kang, Y.J.; Maeda, S.; Yoshida, H.; et al. MicroRNA-140 acts as a liver tumor suppressor by controlling NF-κB activity by directly targeting DNA methyltransferase 1 (DNMT1) expression. Hepatology 2013, 57, 162–170. [Google Scholar] [CrossRef] [PubMed]
  258. Song, B.; Wang, Y.; Xi, Y.; Kudo, K.; Bruheim, S.; Botchkina, G.I.; Gavin, E.; Wan, Y.; Formentini, A.; Kornmann, M.; et al. Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells. Oncogene 2009, 28, 4065–4074. [Google Scholar] [CrossRef] [PubMed]
  259. Ng, E.K.; Tsang, W.P.; Ng, S.S.; Jin, H.C.; Yu, J.; Li, J.J.; Rocken, C.; Ebert, M.P.; Kwok, T.T.; Sung, J.J. MicroRNA-143 targets DNA methyltransferases 3a in colorectal cancer. Br. J. Cancer 2009, 101, 699–706. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  260. Matsui, M.; Chu, Y.; Zhang, H.; Gagnon, K.T.; Shaikh, S.; Kuchimanchi, S.; Manoharan, M.; Corey, D.R.; Janowski, B.A. Promoter RNA links transcriptional regulation of inflammatory pathway genes. Nucleic Acids Res. 2013, 41, 10086–10109. [Google Scholar] [CrossRef] [PubMed]
  261. Zhu, A.; Xia, J.; Zuo, J.; Jin, S.; Zhou, H.; Yao, L.; Huang, H.; Han, Z. MicroRNA-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in gastric cancer. Med. Oncol. 2012, 29, 2701–2709. [Google Scholar] [CrossRef] [PubMed]
  262. Zhang, Z.; Tang, H.; Wang, Z.; Zhang, B.; Liu, W.; Lu, H.; Xiao, L.; Liu, X.; Wang, R.; Li, X.; et al. miR-185 targets the DNA methyltransferases 1 and regulates global DNA methylation in human glioma. Mol. Cancer 2011, 10, 124. [Google Scholar] [CrossRef] [PubMed]
  263. Shimono, Y.; Zabala, M.; Cho, R.W.; Lobo, N.; Dalerba, P.; Qian, D.; Diehn, M.; Liu, H.; Panula, S.P.; Chiao, E.; et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 2009, 138, 592–603. [Google Scholar] [CrossRef] [PubMed]
  264. Bae, H.J.; Jung, K.H.; Eun, J.W.; Shen, Q.; Kim, H.S.; Park, S.J.; Shin, W.C.; Yang, H.D.; Park, W.S.; Lee, J.Y.; et al. MicroRNA-221 governs tumor suppressor hdac6 to potentiate malignant progression of liver cancer. J. Hepatol. 2015, 63, 408–419. [Google Scholar] [CrossRef] [PubMed]
  265. Hwang, H.W.; Wentzel, E.A.; Mendell, J.T. A hexanucleotide element directs microRNA nuclear import. Science 2007, 315, 97–100. [Google Scholar] [CrossRef] [PubMed]
  266. Kim, D.H.; Villeneuve, L.M.; Morris, K.V.; Rossi, J.J. Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells. Nat. Struct. Mol. Biol. 2006, 13, 793–797. [Google Scholar] [CrossRef] [PubMed]
  267. Janowski, B.A.; Huffman, K.E.; Schwartz, J.C.; Ram, R.; Nordsell, R.; Shames, D.S.; Minna, J.D.; Corey, D.R. Involvement of AGO1 and AGO2 in mammalian transcriptional silencing. Nat. Struct. Mol. Biol. 2006, 13, 787–792. [Google Scholar] [CrossRef] [PubMed]
  268. Huang, V.; Zheng, J.; Qi, Z.; Wang, J.; Place, R.F.; Yu, J.; Li, H.; Li, L.C. Ago1 interacts with RNA polymerase ii and binds to the promoters of actively transcribed genes in human cancer cells. PLoS Genet. 2013, 9, e1003821. [Google Scholar] [CrossRef] [PubMed]
  269. Tan, Y.; Zhang, B.; Wu, T.; Skogerbo, G.; Zhu, X.; Guo, X.; He, S.; Chen, R. Transcriptional inhibiton of Hoxd4 expression by miRNA-10a in human breast cancer cells. BMC Mol. Biol. 2009, 10, 12. [Google Scholar] [CrossRef] [PubMed]
  270. Majid, S.; Dar, A.A.; Saini, S.; Yamamura, S.; Hirata, H.; Tanaka, Y.; Deng, G.; Dahiya, R. MicroRNA-205-directed transcriptional activation of tumor suppressor genes in prostate cancer. Cancer 2010, 116, 5637–5649. [Google Scholar] [CrossRef] [PubMed]
  271. Zardo, G.; Ciolfi, A.; Vian, L.; Starnes, L.M.; Billi, M.; Racanicchi, S.; Maresca, C.; Fazi, F.; Travaglini, L.; Noguera, N.; et al. Polycombs and microRNA-223 regulate human granulopoiesis by transcriptional control of target gene expression. Blood 2012, 119, 4034–4046. [Google Scholar] [CrossRef] [PubMed]
  272. Kim, D.H.; Saetrom, P.; Snove, O., Jr.; Rossi, J.J. MicroRNA-directed transcriptional gene silencing in mammalian cells. Proc. Natl. Acad. Sci. USA 2008, 105, 16230–16235. [Google Scholar] [CrossRef] [PubMed]
  273. Place, R.F.; Li, L.C.; Pookot, D.; Noonan, E.J.; Dahiya, R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc. Natl. Acad. Sci. USA 2008, 105, 1608–1613. [Google Scholar] [CrossRef] [PubMed]
  274. Younger, S.T.; Corey, D.R. Transcriptional gene silencing in mammalian cells by miRna mimics that target gene promoters. Nucleic Acids Res. 2011, 39, 5682–5691. [Google Scholar] [CrossRef] [PubMed]
  275. Liu, M.; Roth, A.; Yu, M.; Morris, R.; Bersani, F.; Rivera, M.N.; Lu, J.; Shioda, T.; Vasudevan, S.; Ramaswamy, S.; et al. The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis. Genes Dev. 2013, 27, 2543–2548. [Google Scholar] [CrossRef] [PubMed]
  276. Huang, V.; Place, R.F.; Portnoy, V.; Wang, J.; Qi, Z.; Jia, Z.; Yu, A.; Shuman, M.; Yu, J.; Li, L.C. Upregulation of Cyclin B1 by miRNA and its implications in cancer. Nucleic Acids Res. 2012, 40, 1695–1707. [Google Scholar] [CrossRef] [PubMed]
  277. Morris, K.V.; Chan, S.W.; Jacobsen, S.E.; Looney, D.J. Small interfering RNA-induced transcriptional gene silencing in human cells. Science 2004, 305, 1289–1292. [Google Scholar] [CrossRef] [PubMed]
  278. Weinberg, M.S.; Villeneuve, L.M.; Ehsani, A.; Amarzguioui, M.; Aagaard, L.; Chen, Z.X.; Riggs, A.D.; Rossi, J.J.; Morris, K.V. The antisense strand of small interfering RNAs directs histone methylation and transcriptional gene silencing in human cells. RNA 2006, 12, 256–262. [Google Scholar] [CrossRef] [PubMed]
  279. White, R.J. Rna polymerase III transcription and cancer. Oncogene 2004, 23, 3208–3216. [Google Scholar] [CrossRef] [PubMed]
  280. Osborne, C.K.; Yochmowitz, M.G.; Knight, W.A., 3rd; McGuire, W.L. The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 1980, 46, 2884–2888. [Google Scholar] [CrossRef]
  281. Starnes, L.M.; Sorrentino, A.; Pelosi, E.; Ballarino, M.; Morsilli, O.; Biffoni, M.; Santoro, S.; Felli, N.; Castelli, G.; De Marchis, M.L.; et al. NFI-A directs the fate of hematopoietic progenitors to the erythroid or granulocytic lineage and controls β-globin and G-CSF receptor expression. Blood 2009, 114, 1753–1763. [Google Scholar] [CrossRef] [PubMed]
  282. Janowski, B.A.; Younger, S.T.; Hardy, D.B.; Ram, R.; Huffman, K.E.; Corey, D.R. Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. Nat. Chem. Biol. 2007, 3, 166–173. [Google Scholar] [CrossRef] [PubMed]
  283. Bjornsson, H.T.; Brown, L.J.; Fallin, M.D.; Rongione, M.A.; Bibikova, M.; Wickham, E.; Fan, J.B.; Feinberg, A.P. Epigenetic specificity of loss of imprinting of the IGF2 gene in wilms tumors. J. Natl. Cancer Inst. 2007, 99, 1270–1273. [Google Scholar] [CrossRef] [PubMed]
  284. Jiang, Y.; Qin, Z.; Hu, Z.; Guan, X.; Wang, Y.; He, Y.; Xue, J.; Liu, X.; Chen, J.; Dai, J.; et al. Genetic variation in a hsa-let-7 binding site in RAD52 is associated with breast cancer susceptibility. Carcinogenesis 2013, 34, 689–693. [Google Scholar] [CrossRef] [PubMed]
  285. Esteller, M.; Pandolfi, P.P. The epitranscriptome of noncoding RNAs in cancer. Cancer Discov. 2017, 7, 359–368. [Google Scholar] [CrossRef] [PubMed]
  286. Jacob, R.; Zander, S.; Gutschner, T. The dark side of the epitranscriptome: Chemical modifications in long non-coding RNAs. Int. J. Mol. Sci. 2017, 18, 2387. [Google Scholar] [CrossRef] [PubMed]
  287. Alarcon, C.R.; Lee, H.; Goodarzi, H.; Halberg, N.; Tavazoie, S.F. N6-methyladenosine marks primary microRNAs for processing. Nature 2015, 519, 482–485. [Google Scholar] [CrossRef] [PubMed]
  288. Wang, Y.; Xu, X.; Yu, S.; Jeong, K.J.; Zhou, Z.; Han, L.; Tsang, Y.H.; Li, J.; Chen, H.; Mangala, L.S.; et al. Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers. Genome Res. 2017, 27, 1112–1125. [Google Scholar] [CrossRef] [PubMed]
  289. Monnier, P.; Martinet, C.; Pontis, J.; Stancheva, I.; Ait-Si-Ali, S.; Dandolo, L. H19 lncRNA controls gene expression of the imprinted gene network by recruiting MBD1. Proc. Natl. Acad. Sci. USA 2013, 110, 20693–20698. [Google Scholar] [CrossRef] [PubMed]
  290. Kallen, A.N.; Zhou, X.B.; Xu, J.; Qiao, C.; Ma, J.; Yan, L.; Lu, L.; Liu, C.; Yi, J.S.; Zhang, H.; et al. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol. Cell 2013, 52, 101–112. [Google Scholar] [CrossRef] [PubMed]
  291. Chiyomaru, T.; Fukuhara, S.; Saini, S.; Majid, S.; Deng, G.; Shahryari, V.; Chang, I.; Tanaka, Y.; Enokida, H.; Nakagawa, M.; et al. Long non-coding rna hotair is targeted and regulated by miR-141 in human cancer cells. J. Biol. Chem. 2014, 289, 12550–12565. [Google Scholar] [CrossRef] [PubMed]
  292. Cai, H.; Yao, J.; An, Y.; Chen, X.; Chen, W.; Wu, D.; Luo, B.; Yang, Y.; Jiang, Y.; Sun, D.; et al. LncRNA HOTAIR acts a competing endogenous RNA to control the expression of Notch3 via sponging miR-613 in pancreatic cancer. Oncotarget 2017, 8, 32905–32917. [Google Scholar] [CrossRef] [PubMed]
  293. Tsai, M.C.; Manor, O.; Wan, Y.; Mosammaparast, N.; Wang, J.K.; Lan, F.; Shi, Y.; Segal, E.; Chang, H.Y. Long noncoding RNA as modular scaffold of histone modification complexes. Science 2010, 329, 689–693. [Google Scholar] [CrossRef] [PubMed]
Ijms 19 00459 g001 550
Figure 1. Feedback circuit between microRNAs and epigenetic machinery. The epigenetic modification, such as promoter CpG island hyper- or hypo-methylation and/or histone modifications, affect miRNAs and genes transcription. MiRNAs can themselves regulate the epigenetic machinery by post-transcriptional gene silencing (PTGS), targeting DNMTs, HDACs, and the histone methyl-transferases (HMTs), establishing epigenetic pathway loops. In the figure, black lines represent the pathway starting from the epigenetic modifications and ending with the miRNAs maturation, while blue lines represent the pathway from the mature miRNA to the post transcriptional gene silencing of the epigenetic machinery.
Figure 1. Feedback circuit between microRNAs and epigenetic machinery. The epigenetic modification, such as promoter CpG island hyper- or hypo-methylation and/or histone modifications, affect miRNAs and genes transcription. MiRNAs can themselves regulate the epigenetic machinery by post-transcriptional gene silencing (PTGS), targeting DNMTs, HDACs, and the histone methyl-transferases (HMTs), establishing epigenetic pathway loops. In the figure, black lines represent the pathway starting from the epigenetic modifications and ending with the miRNAs maturation, while blue lines represent the pathway from the mature miRNA to the post transcriptional gene silencing of the epigenetic machinery.
Ijms 19 00459 g001
Ijms 19 00459 g002 550
Figure 2. MicroRNAs regulate gene transcription. Nuclear miRNAs can mediate both transcriptional gene silencing (TGS) and transcriptional gene activation (TGA) by targeting gene promoters. During the TGS, AGO1, DICER, EZH2, SUZ12, and YY1 proteins can be recruited on target promoters to induce the silencing through enrichment of H3K9me3 and H3K27me3. Instead, during the TGA, target promoters exhibit the enrichment of the RNA polymerase II, H3K4me3, and H3ac, H4ac; moreover, AGO1 was also found to be associated to target promoters during TGA. In the figure, black arrows indicate the miRNAs biogenesis pathway, and red and blue lines represent miRNAs translocated back to the nucleus to mediate TGS or TGA, respectively. Chromatin modifications are represented in bold.
Figure 2. MicroRNAs regulate gene transcription. Nuclear miRNAs can mediate both transcriptional gene silencing (TGS) and transcriptional gene activation (TGA) by targeting gene promoters. During the TGS, AGO1, DICER, EZH2, SUZ12, and YY1 proteins can be recruited on target promoters to induce the silencing through enrichment of H3K9me3 and H3K27me3. Instead, during the TGA, target promoters exhibit the enrichment of the RNA polymerase II, H3K4me3, and H3ac, H4ac; moreover, AGO1 was also found to be associated to target promoters during TGA. In the figure, black arrows indicate the miRNAs biogenesis pathway, and red and blue lines represent miRNAs translocated back to the nucleus to mediate TGS or TGA, respectively. Chromatin modifications are represented in bold.
Ijms 19 00459 g002
Table
Table 1. Epigenetically regulated miRNAs in human cancer.
Table 1. Epigenetically regulated miRNAs in human cancer.
miRNACancer TypeEpigenetic ModificationTargetReference
miR-1Hepatocellular, liver, colorectal, lungDMhyperFOXP1, MET, HDAC4, Pim1[74,121,122]
miR-9Breast, ovarian, pancreatic, multiple myeloma, renal, gastric, hepatocellular, colorectal, melanoma, head and neck, multiple myeloma, lungDMhyperCCNG1, IL-6, AP3B1, TC10, ONECUT2, IGF2BP1, MYO1D, ANXA2[44,47,58,67,75,123,124,125]
miR-10aGastric, bladder, hepatocellularDMhyperHOXA1[69,126,127]
miR-10bGastric, hepatocellularDMhyper [70,127]
miR-15a/16Chronic lymphocytic leukemia, mantle cell lymphomaHDABCL2, MCL1[109,110]
miR-17-92Colorectal HDAPTEN, BCL2L11, CDKN1A[128]
miR-21Ovarian, prostate, colorectalDMhypo, DMhyper, HMTITGB4[129,130,131]
miR-23a-27aHepatocellularDMhypo [78]
miR-24NasopharyngealDMhyper [132]
miR-29a/bB-cell Lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, lungHMT, HDAMCL1, DNMT3A-B[31,32,109,133,134]
miR-31Melanoma, prostate, breastHMT, DMhyper, HDASRC, RAB27A, MAP3K14, MET, E2F1, E2F2, EXO1, FOXM1, MCM2, E2F6, BMI-1[120,135,136,137,138,139]
miR-33bGastricDMhyper [72]
miR-34aLung, breast, colon, kidney, bladder, pancreatic cancer cells, melanomaDMhyperCDK6[76,140,141]
miR-34b/cGastric, ovarian, lung, colon, melanoma, head and neck, breast, non-small cell lung, neuroblastoma, hepatocellular, pleural mesothelioma, oralDMhyperMYC, CDK6, E2F3[45,68,76,141,142,143,144,145]
miR-101HepatocellularHMT [118]
miR-106b-25-93 HepatocellularDMhypo [78]
miR-107PancreaticDMhyperCDK6[146]
miR-124Colon, gastric, hematological, cervical, glioblastoma cells, breast, prostate, neuroblastoma, pancreatic, colorectal, non-small cell lung, acute lymphoblastic leukemia, hepatocellular, renalDMhyperBCL2, CDK6, VIM, SMYD3, IQGAP1, RAC1[45,59,73,77,142,144,147,148,149,150,151,152]
miR-125bBreast, hepatocellularHMT, DMhyperPGF[45,118,153]
miR-126Bladder, malignant pleural mesothelioma, colorectal, non-small cell lungDMhyper, HDAVEGF[154,155,156,157]
miR-127Prostate, bladder, colon, breast, clear cell renal cell carcinomaDMhyper, HDADAPK1, BCL6[42,45,158]
miR-129Gastric, endometrial, colorectal, hepatocellular, hematologicalDMhyperSOX4[68,159,160,161,162,163]
miR-132Pancreas, prostate, breastDMhyper, HDATALIN2, HB-EGF[45,164,165]
miR-133bColorectalDMhyper [166]
miR-137Head and neck squamous cells, colorectal, glioblastoma cells, prostate, multiple myeloma, gastric, oral, hepatocellular cellsDMhyperCDK6, E2F6, LSD-1, ASCT2, AURKA[98,145,151,167,168,169,170,171]
miR-139Hepatocellular, non-small cell lungHMTROCK2[172,173]
miR-141Clear cell renal cell carcinomaDMhyper, HDATET1, TET3, ZEB1[158,174]
miR-143LeukemiaDMhyperMLL-AF4[175]
miR-145Prostate, lung adenocarcinoma, non-small cell carcinoma, clear cell renal cell carcinomaDMhyper, HDATNFSF10, MUCIN1[158,176,177,178,179]
miR-148aColorectal, melanoma, head and neck, breast, pancreas, hepatocellularDMhyperTGIF2[44,78]
miR-149BreastDMhyperNDST1[57]
miR-152Endometrium, bladder cancer cells, prostate, breast cancer cellsDMhyperDNMT1, E2F3, MET, RICTOR[34,126,171,180,181]
miR-155Breast, prostateHDA, DMhyper [113,171]
miR-181a/bProstateHMT, DMhyper, HDARING2[119]
miR-181cGastric, prostate, glioblastoma cells DMhyper NOTCH4, KRAS, NOTCH2[65,182]
miR-191Breast, hepatocellularDMhypoTIMP3[45,183]
miR-192Pancreatic ductal adenocarcinomaDMhyperSERPINE1[61]
miR-193aHepatocellular, acute myeloid leukemia, bladder, breast, oralDMhyper, DMhypoE2F6, SRSF2, PLAU, HIC2[45,145,184,185,186]
miR-193bProstateDMhyper, HDA [187,188]
miR-195/497HepatocellularDMhyper [78]
miR-196bGastric, prostate, hepatocellularDMhyper, DMhypo [127,131,189]
miR-199aTesticular, ovarianDMhyperPODXL, DDR1[190,191]
miR-200a/b/429Hepatocellular, prostate, gastric, glioblastoma, pancreatic, bladderHMT, DMhyper, HDA, DMhypoBMI1, RING2[63,71,118,119,126,192]
miR-200c/141Colon, breast, lung, prostate, non-small cell lungHMT, DMhyper, HDADNMT3A TET1, TET3, BMI1, RING2, SOX2, ZEB1, DNMT3A[119,174,193,194,195]
miR-203Hematological, hepatocellular, endometrial, ovarian, prostate, oralDMhyper, DMhypo, HMT, HDAABCE1, BMI1, SOX4[77,119,129,145,196,197]
miR-205Bladder, prostate, ovarianDMhypo, DMhyperBCL2L2[129,131,139,198]
miR-218Oral squamous cell carcinomaDMhyperRICTOR[199]
miR-219aGastric, endometrialDMhyper [196,200]
miR-221HepatocellularDMhypoMDM2[81]
miR-224HepatocellularHDA, HAT [116]
miR-335Breast, hepatocellular, gastricDMhyperRASA1, CRKL[201,202,203,204]
miR-342ColorectalDMhyper [205]
miR-345ColorectalDMhyperBAG3[206]
miR-370Cholangiocarcinoma, oral squamous cellsDMhyperIRS1[207,208]
miR-373CholangiocarcinomaDMhyper, HDA [209]
miR-375Esophagus, melanoma, prostate, hepatocellular, breastDMhyperRASFF1(A), PDK1[45,78,210,211,212]
miR-376cCholangiocarcinomaDMhyper [207]
miR-378HepatocellularDMhyper [78]
miR-449a/bOsteosarcoma cell line, breast cell line, hepatocellularHMT, HDACDK6, CDC25A, C-MET[115,117]
miR-512GastricDMhyper, HDA [42]
miR-514Clear cell renal cell carcinomaDMhyper, HDA [158]
miR-585Oral squamous cell carcinomaDMhyper [199]
miR-596EndometrialDMhyper [196]
miR-615Pancreatic ductal adenocarcinomaDMhypoIGF2[60,131]
miR-618EndometrialDMhyper [196]
miR-874BreastDMhyper [213]
miR-941Colorectal cells DMhyper [214,215]
miR-1224BladderDMhyper [214,216]
miR-1237Colorectal cells DMhyper [214]
miR-1247Colorectal and gastric cells, pancreatic, non-small cell lungDMhyperRARA, STX1B, RCC2[62,214,215,217]
Let-7aOvarian, acute myeloid leukemia, lung, nasopharyngeal carcinoma cellsDMhyper, DMhypoC-MYC[218,219,220,221]
Let-7cHepatocellularHMT [118]
DMhyper: DNA hyper-methylation; DMhypo: DNA hypo-methylation; HMT: histone methyl-transferase; HDA: histone de-acetilase; HAT: histone acetyl-trasferase. Targets are referred to epigenetically modified miRNAs.
Table
Table 2. MicroRNAs target epigenetic complex at post-transcriptional level.
Table 2. MicroRNAs target epigenetic complex at post-transcriptional level.
MicroRNAsTargetCancer TypeReference
miR-15a/16-1BMIOvarian[244]
miR-26aEZH2Burkit lymphoma[238]
miR-29a/bDNMT3A-B, DNMT1Lung, acute myeloid leukemia, hepatocellular [31,32,228]
miR-30aHP1γColorectal[255]
miR-101EZH2Prostate, bladder transitional cell carcinoma[239,240]
miR-128BMI, SUZ12 Glioma[235,243]
miR-137EZH2Cervical [256]
miR-140DNMT1, HDAC4Hepatocellular, osteosarcoma, colorectal [257,258]
miR-143DNMT3AColorectal[259]
miR-145HDAC2Hepatocellular [260]
miR-148DNMT3BCervical cancer cells[229]
miR-148aDNMT1Cholangiocarcinoma, gastric [34,261]
miR-152DNMT1Cholangioarcinoma, breast[34,181]
miR-155HDAC4B-cells lymphoma[252]
miR-185DNMT1Glioma [262]
miR-194BMIEndometrial [245]
miR-200bSUZ12, BMIBreast, hepatocellular[192,234]
miR-200cBMIBreast [263]
miR-203BMIMultiple myeloma[247]
miR-218BMIGlioma[246]
miR-221HDAC6Liver [264]
miR-449aHDAC1Prostate[250]
miR-K12-4-5pRBL2Kaposi’s sarcoma-associated herpesvirus[33]
Table
Table 3. MicroRNAs acting as transcriptional regulator.
Table 3. MicroRNAs acting as transcriptional regulator.
MicroRNATargetTGS/TGAReference
miR-10aHOXD4TGS[269]
miR-205IL24TGA[270]
miR-205IL32TGA[270]
miR-223NFI-ATGS[271]
miR-320POLR3DTGS[272]
miR-373CDH1TGA[273]
miR-373CSDC2TGA[273]
miR-423 (synthetic)PRTGS[274]
miR-483IGF2TGA[275]
miR-589COX2TGA[260]
miR-774Cnnb1TGA[276]
miR-1186Cnnb1TGA[276]

Share and Cite

MDPI and ACS Style

Ramassone, A.; Pagotto, S.; Veronese, A.; Visone, R. Epigenetics and MicroRNAs in Cancer. Int. J. Mol. Sci. 2018, 19, 459. https://doi.org/10.3390/ijms19020459

AMA Style

Ramassone A, Pagotto S, Veronese A, Visone R. Epigenetics and MicroRNAs in Cancer. International Journal of Molecular Sciences. 2018; 19(2):459. https://doi.org/10.3390/ijms19020459

Chicago/Turabian Style

Ramassone, Alice, Sara Pagotto, Angelo Veronese, and Rosa Visone. 2018. "Epigenetics and MicroRNAs in Cancer" International Journal of Molecular Sciences 19, no. 2: 459. https://doi.org/10.3390/ijms19020459

APA Style

Ramassone, A., Pagotto, S., Veronese, A., & Visone, R. (2018). Epigenetics and MicroRNAs in Cancer. International Journal of Molecular Sciences, 19(2), 459. https://doi.org/10.3390/ijms19020459

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop