International Journal of Molecular Sciences

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Open AccessArticle

Comprehensive Evaluation of TFF3 Promoter Hypomethylation and Molecular Biomarker Potential for Prostate Cancer Diagnosis and Prognosis

by Maibritt Nørgaard, Christa Haldrup, Tine Maj Storebjerg, Else Marie Vestergaard, Peter J. Wild, Søren Høyer, Michael Borre, Torben Falck Ørntoft and Karina Dalsgaard Sørensen

Int. J. Mol. Sci. 2017, 18(9), 2017; https://doi.org/10.3390/ijms18092017 - 20 Sep 2017

Cited by 14 | Viewed by 4995

Abstract

Overdiagnosis and overtreatment of clinically insignificant tumors remains a major problem in prostate cancer (PC) due to suboptimal diagnostic and prognostic tools. Thus, novel biomarkers are urgently needed. In this study, we investigated the biomarker potential of Trefoil factor 3 (TFF3) [...] Read more.

Overdiagnosis and overtreatment of clinically insignificant tumors remains a major problem in prostate cancer (PC) due to suboptimal diagnostic and prognostic tools. Thus, novel biomarkers are urgently needed. In this study, we investigated the biomarker potential of Trefoil factor 3 (TFF3) promoter methylation and RNA expression levels for PC. Initially, by quantitative methylation specific PCR (qMSP) analysis of a large radical prostatectomy (RP) cohort (n = 292), we found that the TFF3 promoter was significantly hypomethylated in PC compared to non-malignant (NM) prostate tissue samples (p < 0.001) with an AUC (area under the curve) of 0.908 by receiver operating characteristics (ROC) curve analysis. Moreover, significant TFF3 promoter hypomethylation (p ≤ 0.010) as well as overexpression (p < 0.001) was found in PC samples from another large independent patient sample set (498 PC vs. 67 NM) analyzed by Illumina 450K DNA methylation arrays and/or RNA sequencing. TFF3 promoter methylation and transcriptional expression levels were inversely correlated, suggesting that epigenetic mechanisms contribute to the regulation of gene activity. Furthermore, low TFF3 expression was significantly associated with high ERG, ETS transcription factor (ERG) expression (p < 0.001), as well as with high Gleason score (p < 0.001), advanced pathological T-stage (p < 0.001), and prostate-specific antigen (PSA) recurrence after RP (p = 0.013; univariate Cox regression analysis). There were no significant associations between TFF3 promoter methylation levels, ERG status, or PSA recurrence in these RP cohorts. In conclusion, our results demonstrated diagnostic biomarker potential of TFF3 promoter hypomethylation for PC as well as prognostic biomarker potential of TFF3 RNA expression. To the best of our knowledge, this is the most comprehensive study of TFF3 promoter methylation and transcriptional expression in PC to date. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Open AccessArticle

Reprimo, a Potential p53-Dependent Tumor Suppressor Gene, Is Frequently Hypermethylated in Estrogen Receptor α-Positive Breast Cancer

by Kurt Buchegger, Ismael Riquelme, Tamara Viscarra, Carmen Ili, Priscilla Brebi, Tim Hui-Ming Huang and Juan Carlos Roa

Int. J. Mol. Sci. 2017, 18(8), 1525; https://doi.org/10.3390/ijms18081525 - 15 Aug 2017

Cited by 8 | Viewed by 5101

Abstract

Aberrant DNA methylation is a hallmark of many cancers. Currently, there are four intrinsic molecular subtypes in breast cancer (BC): Luminal A, B, Her2-positive, and triple negative (TNBC). Recently, The Cancer Genome Atlas (TCGA) project has revealed that Luminal subtypes have higher levels [...] Read more.

Aberrant DNA methylation is a hallmark of many cancers. Currently, there are four intrinsic molecular subtypes in breast cancer (BC): Luminal A, B, Her2-positive, and triple negative (TNBC). Recently, The Cancer Genome Atlas (TCGA) project has revealed that Luminal subtypes have higher levels of genome-wide methylation that may be a result of Estrogen/Estrogen receptor α (E2/ERα) signaling pathway activation. In this study, we analyze promoter CpG-island (CGIs) of the Reprimo (RPRM) gene in breast cancers (n = 77), cell lines (n = 38), and normal breast tissue (n = 10) using a MBDCap-seq database. Then, a validation cohort (n = 26) was used to confirm the results found in the MBDCap-seq platform. A differential methylation pattern was found between BC and cell lines compared to normal breast tissue. In BC, a higher DNA methylation was observed in tissues that were ERα-positive than in ERα-negative ones; more precisely, subtypes Luminal A compared to TNBC. Also, significant reverse correlation was observed between DNA methylation and RPRM mRNA expression in BC. Our data suggest that ERα expression in BC may affect the DNA methylation of CGIs in the RPRM gene. This approach suggests that DNA methylation status in CGIs of some tumor suppressor genes could be driven by E2 availability, subsequently inducing the activation of the ERα pathway. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Open AccessArticle

Taxifolin Activates the Nrf2 Anti-Oxidative Stress Pathway in Mouse Skin Epidermal JB6 P+ Cells through Epigenetic Modifications

by Haixue Kuang, Zhenqiu Tang, Chengyue Zhang, Zhibin Wang, Wenji Li, Chunjuan Yang, Qiuhong Wang, Bingyou Yang and Ah-Ng Kong

Int. J. Mol. Sci. 2017, 18(7), 1546; https://doi.org/10.3390/ijms18071546 - 17 Jul 2017

Cited by 49 | Viewed by 6102

Abstract

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a vital transcription factor that regulates the anti-oxidative defense system. Previous reports suggested that the expression of the Nrf2 gene can be regulated by epigenetic modifications. The potential epigenetic effect of taxifolin (TAX), a potent [...] Read more.

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a vital transcription factor that regulates the anti-oxidative defense system. Previous reports suggested that the expression of the Nrf2 gene can be regulated by epigenetic modifications. The potential epigenetic effect of taxifolin (TAX), a potent cancer chemopreventive agent, in skin cancer chemoprotection is unknown. In this study, we investigated how Nrf2 is epigenetically regulated by TAX in JB6 P+ cells. TAX was found to inhibit the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced colony formation of JB6 P+ cells. TAX induced antioxidant response element (ARE)-luciferase activity in HepG2-C8 cells and up-regulated mRNA and protein levels of Nrf2 and its downstream genes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1), in JB6 P+ cells. Furthermore, bisulfite genomic sequencing revealed that TAX treatment reduces the methylation level of the first 15 CpGs sites in the Nrf2 promoter. Western blotting showed that TAX inhibits the expression levels of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) proteins. In summary, our results revealed that TAX can induce expression of Nrf2 and its downstream target genes in JB6 P+ cells by CpG demethylation. These finding suggest that TAX may exhibit a skin cancer preventive effect by activating Nrf2 via an epigenetic pathway. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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A Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells

by Kendra J. Royston, Neha Udayakumar, Kayla Lewis and Trygve O. Tollefsbol

Int. J. Mol. Sci. 2017, 18(5), 1092; https://doi.org/10.3390/ijms18051092 - 19 May 2017

Cited by 72 | Viewed by 8849

Abstract

With cancer often classified as a disease that has an important epigenetic component, natural compounds that have the ability to regulate the epigenome become ideal candidates for study. Humans have a complex diet, which illustrates the need to elucidate the mechanisms of interaction [...] Read more.

With cancer often classified as a disease that has an important epigenetic component, natural compounds that have the ability to regulate the epigenome become ideal candidates for study. Humans have a complex diet, which illustrates the need to elucidate the mechanisms of interaction between these bioactive compounds in combination. The natural compounds withaferin A (WA), from the Indian winter cherry, and sulforaphane (SFN), from cruciferous vegetables, have numerous anti-cancer effects and some report their ability to regulate epigenetic processes. Our study is the first to investigate the combinatorial effects of low physiologically achievable concentrations of WA and SFN on breast cancer cell proliferation, histone deacetylase1 (HDAC1) and DNA methyltransferases (DNMTs). No adverse effects were observed on control cells at optimal concentrations. There was synergistic inhibition of cellular viability in MCF-7 cells and a greater induction of apoptosis with the combinatorial approach than with either compound administered alone in both MDA-MB-231 and MCF-7 cells. HDAC expression was down-regulated at multiple levels. Lastly, we determined the combined effects of these bioactive compounds on the pro-apoptotic BAX and anti-apoptotic BCL-2 and found decreases in BCL-2 and increases in BAX. Taken together, our findings demonstrate the ability of low concentrations of combinatorial WA and SFN to promote cancer cell death and regulate key epigenetic modifiers in human breast cancer cells. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Open AccessArticle

The Regulatory Capacity of Bivalent Genes—A Theoretical Approach

by Torsten Thalheim, Maria Herberg, Markus Loeffler and Joerg Galle

Int. J. Mol. Sci. 2017, 18(5), 1069; https://doi.org/10.3390/ijms18051069 - 17 May 2017

Cited by 10 | Viewed by 4787

Abstract

Bivalent genes are frequently associated with developmental and lineage specification processes. Resolving their bivalency enables fast changes in their expression, which potentially can trigger cell fate decisions. Here, we provide a theoretical model of bivalency that allows for predictions on the occurrence, stability [...] Read more.

Bivalent genes are frequently associated with developmental and lineage specification processes. Resolving their bivalency enables fast changes in their expression, which potentially can trigger cell fate decisions. Here, we provide a theoretical model of bivalency that allows for predictions on the occurrence, stability and regulatory capacity of this prominent modification state. We suggest that bivalency enables balanced gene expression heterogeneity that constitutes a prerequisite of robust lineage priming in somatic stem cells. Moreover, we demonstrate that interactions between the histone and DNA methylation machineries together with the proliferation activity control the stability of the bivalent state and can turn it into an unmodified state. We suggest that deregulation of these interactions underlies cell transformation processes as associated with acute myeloid leukemia (AML) and provide a model of AML blast formation following deregulation of the Ten-eleven Translocation (TET) pathway. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Histone H3 Acetyl K9 and Histone H3 Tri Methyl K4 as Prognostic Markers for Patients with Cervical Cancer

by Susanne Beyer, Junyan Zhu, Doris Mayr, Christina Kuhn, Sandra Schulze, Simone Hofmann, Christian Dannecker, Udo Jeschke and Bernd P. Kost

Int. J. Mol. Sci. 2017, 18(3), 477; https://doi.org/10.3390/ijms18030477 - 23 Feb 2017

Cited by 45 | Viewed by 5845

Abstract

Chromatin remodeling alters gene expression in carcinoma tissue. Although cervical cancer is the fourth most common cancer in women worldwide, a systematic study about the prognostic value of specific changes in the chromatin structure, such as histone acetylation or histone methylation, is missing. [...] Read more.

Chromatin remodeling alters gene expression in carcinoma tissue. Although cervical cancer is the fourth most common cancer in women worldwide, a systematic study about the prognostic value of specific changes in the chromatin structure, such as histone acetylation or histone methylation, is missing. In this study, the expression of histone H3 acetyl K9, which is known to denote active regions at enhancers and promoters, and histone H3 tri methyl K4, which preferentially identifies active gene promoters, were examined as both show high metastatic potential. A panel of patients with cervical cancer was selected and the importance of the histone modifications concerning survival-time (overall survival and relapse-free survival) was analyzed in 250 cases. Histone H3 acetyl K9 staining was correlated with low grading, low FIGO (TNM classification and the International Federation of Gynecology and Obstetrics) status, negative N-status and low T-status in cervical cancer, showing a higher expression in adenocarcinoma than in squamous cell carcinoma. Cytoplasmic expression of histone H3 tri methyl K4 in a cervical cancer specimen was correlated with advanced T-status and poor prognosis. While cytoplasmic H3K4me3 expression seemed to be a marker of relapse-free survival, nuclear expression showed a correlation to poor prognosis in overall survival. Within this study, we analyzed the chemical modification of two histone proteins that are connected to active gene expression. Histone H3 acetyl K9 was found to be an independent marker of overall survival. Histone H3 tri methyl K4 was correlated with poor prognosis and it was found to be an independent marker of relapse-free survival. Therefore, we could show that chromatin remodeling plays an important role in cervical cancer biology. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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mir-660-p53-mir-486 Network: A New Key Regulatory Pathway in Lung Tumorigenesis

by Cristina Borzi, Linda Calzolari, Giovanni Centonze, Massimo Milione, Gabriella Sozzi and Orazio Fortunato

Int. J. Mol. Sci. 2017, 18(1), 222; https://doi.org/10.3390/ijms18010222 - 23 Jan 2017

Cited by 28 | Viewed by 7051

Abstract

Lung cancer is the most frequent cause of cancer-related death worldwide, with limited therapeutic options and rapid development of drug resistance. MicroRNAs, a class of small non-coding RNAs that control different physiological processes, have been associated with cancer development, as either oncomiRNAs or [...] Read more.

Lung cancer is the most frequent cause of cancer-related death worldwide, with limited therapeutic options and rapid development of drug resistance. MicroRNAs, a class of small non-coding RNAs that control different physiological processes, have been associated with cancer development, as either oncomiRNAs or tumor-suppressor miRNAs. In the present study we investigated the interaction between mir-486-5p and mir-660-5p, two independent tumor-suppressor miRNAs, to assess their possible role and synergistic effect in lung cancer treatment. Our data show that mir-660-5p over-expression in A549 lung cancer cells induced a remarkable increase in mir-486-5p expression level and activity, detected as a reduction of its target gene, p85. mir-486-5p expression was confirmed by microRNA in situ hybridization. mir-660-5p modulated mir-486-5p through the silencing of Mouse Double Minute 2 (MDM2), one of its direct target, and then through p53 stimulation. This regulatory pathway was effective in A549, but not in H1299; therefore, only in the context of a functional p53 protein. Our findings support the conclusion that mir-486-5p is positively regulated by mir-660-5p in lung cancer cell lines, through the mir-660-MDM2-p53 pathway, making mir-660-5p even more interesting for its potential successful use in lung cancer therapy. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Integrated MicroRNA–mRNA Profiling Identifies Oncostatin M as a Marker of Mesenchymal-Like ER-Negative/HER2-Negative Breast Cancer

by Giulia Bottai, Lixia Diao, Keith A. Baggerly, Laura Paladini, Balázs Győrffy, Carlotta Raschioni, Lajos Pusztai, George A. Calin and Libero Santarpia

Int. J. Mol. Sci. 2017, 18(1), 194; https://doi.org/10.3390/ijms18010194 - 19 Jan 2017

Cited by 17 | Viewed by 6056

Abstract

MicroRNAs (miRNAs) simultaneously modulate different oncogenic networks, establishing a dynamic system of gene expression and pathway regulation. In this study, we analyzed global miRNA and messenger RNA (mRNA) expression profiles of 17 cell lines representing different molecular breast cancer subtypes. Spearman’s rank correlation [...] Read more.

MicroRNAs (miRNAs) simultaneously modulate different oncogenic networks, establishing a dynamic system of gene expression and pathway regulation. In this study, we analyzed global miRNA and messenger RNA (mRNA) expression profiles of 17 cell lines representing different molecular breast cancer subtypes. Spearman’s rank correlation test was used to evaluate the correlation between miRNA and mRNA expression. Hierarchical clustering and pathway analysis were also performed. Publicly available gene expression profiles (n = 699) and tumor tissues (n = 80) were analyzed to assess the relevance of key miRNA-regulated pathways in human breast cancer. We identified 39 significantly deregulated miRNAs, and the integration between miRNA and mRNA data revealed the importance of immune-related pathways, particularly the Oncostatin M (OSM) signaling, associated with mesenchymal-like breast cancer cells. OSM levels correlated with genes involved in the inflammatory response, epithelial-to-mesenchymal transition (EMT), and epidermal growth factor (EGF) signaling in human estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Our results suggest that the deregulation of specific miRNAs may cooperatively impair immune and EMT pathways. The identification of the OSM inflammatory pathway as an important mediator of EMT in triple-negative breast cancer (TNBC) may provide a novel potential opportunity to improve therapeutic strategies. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Aberrant JAK/STAT Signaling Suppresses TFF1 and TFF2 through Epigenetic Silencing of GATA6 in Gastric Cancer

by Cheng-Shyong Wu, Kuo-Liang Wei, Jian-Liang Chou, Chung-Kuang Lu, Ching-Chuan Hsieh, Jora M. J. Lin, Yi-Fang Deng, Wan-Ting Hsu, Hui-Min David Wang, Chung-Hang Leung, Dik-Lung Ma, Chin Li and Michael W. Y. Chan

Int. J. Mol. Sci. 2016, 17(9), 1467; https://doi.org/10.3390/ijms17091467 - 2 Sep 2016

Cited by 26 | Viewed by 6125

Abstract

Aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is crucial to the development of gastric cancer. In this study, we examined the role of STAT3 in the expression and methylation of its targets in gastric cancer patients. Results from RNA [...] Read more.

Aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is crucial to the development of gastric cancer. In this study, we examined the role of STAT3 in the expression and methylation of its targets in gastric cancer patients. Results from RNA sequencing identified an inverse correlation between the expression of STAT3 and GATA6 in 23 pairs of gastric cancer patient samples. We discovered that the expression of GATA6 is epigenetically silenced through promoter methylation in gastric cancer cell lines. Interestingly, the inhibition of STAT3 using a novel STAT3 inhibitor restored the expression of GATA6 and its targets, trefoil factors 1 and 2 (TFF1/2). Moreover, disruption of STAT3 binding to GATA6 promoter by small hairpin RNA restored GATA6 expression in AGS cells. A clinically significant correlation was also observed between the expression of GATA6 and TFF1/2 among tissue samples from 60 gastric cancer patients. Finally, bisulfite pyrosequencing revealed GATA6 methylation in 65% (39/60) of the patients, and those with higher GATA6 methylation tended to have shorter overall survival. In conclusion, we demonstrated that aberrant JAK/STAT signaling suppresses TFF1/2 partially through the epigenetic silencing of GATA6. Therapeutic intervention of STAT3 in reversing the epigenetic status of GATA6 could benefit the treatment of gastric cancer and is worthy of further investigation. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Review

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Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma

by Ali Mehdi and Yasser Riazalhosseini

Int. J. Mol. Sci. 2017, 18(8), 1774; https://doi.org/10.3390/ijms18081774 - 16 Aug 2017

Cited by 47 | Viewed by 10332

Abstract

Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau (VHL) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which [...] Read more.

Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau (VHL) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC. Although VHL mutations are considered as drivers of ccRCC, they are not sufficient to cause the disease. Recent genome-wide sequencing studies of ccRCC have revealed that mutations of genes coding for epigenome modifiers and chromatin remodelers, including PBRM1, SETD2 and BAP1, are the most common somatic genetic abnormalities after VHL mutations in these tumors. Moreover, recent research has shed light on the extent of abnormal epigenome alterations in ccRCC tumors, including aberrant DNA methylation patterns, abnormal histone modifications and deregulated expression of non-coding RNAs. In this review, we discuss the epigenetic modifiers that are commonly mutated in ccRCC, and our growing knowledge of the cellular processes that are impacted by them. Furthermore, we explore new avenues for developing therapeutic approaches based on our knowledge of epigenome aberrations of ccRCC. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Epigenetic Modifications and Head and Neck Cancer: Implications for Tumor Progression and Resistance to Therapy

by Rogerio M. Castilho, Cristiane H. Squarize and Luciana O. Almeida

Int. J. Mol. Sci. 2017, 18(7), 1506; https://doi.org/10.3390/ijms18071506 - 12 Jul 2017

Cited by 121 | Viewed by 9335

Abstract

Head and neck squamous carcinoma (HNSCC) is the sixth most prevalent cancer and one of the most aggressive malignancies worldwide. Despite continuous efforts to identify molecular markers for early detection, and to develop efficient treatments, the overall survival and prognosis of HNSCC patients [...] Read more.

Head and neck squamous carcinoma (HNSCC) is the sixth most prevalent cancer and one of the most aggressive malignancies worldwide. Despite continuous efforts to identify molecular markers for early detection, and to develop efficient treatments, the overall survival and prognosis of HNSCC patients remain poor. Accumulated scientific evidences suggest that epigenetic alterations, including DNA methylation, histone covalent modifications, chromatin remodeling and non-coding RNAs, are frequently involved in oral carcinogenesis, tumor progression, and resistance to therapy. Epigenetic alterations occur in an unsystematic manner or as part of the aberrant transcriptional machinery, which promotes selective advantage to the tumor cells. Epigenetic modifications also contribute to cellular plasticity during tumor progression and to the formation of cancer stem cells (CSCs), a small subset of tumor cells with self-renewal ability. CSCs are involved in the development of intrinsic or acquired therapy resistance, and tumor recurrences or relapse. Therefore, the understanding and characterization of epigenetic modifications associated with head and neck carcinogenesis, and the prospective identification of epigenetic markers associated with CSCs, hold the promise for novel therapeutic strategies to fight tumors. In this review, we focus on the current knowledge on epigenetic modifications observed in HNSCC and emerging Epi-drugs capable of sensitizing HNSCC to therapy. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Open AccessReview

Histone Deacetylase Inhibitors as Anticancer Drugs

by Tomas Eckschlager, Johana Plch, Marie Stiborova and Jan Hrabeta

Int. J. Mol. Sci. 2017, 18(7), 1414; https://doi.org/10.3390/ijms18071414 - 1 Jul 2017

Cited by 897 | Viewed by 24947

Abstract

Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC [...] Read more.

Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Epigenetic Regulation of the Biosynthesis & Enzymatic Modification of Heparan Sulfate Proteoglycans: Implications for Tumorigenesis and Cancer Biomarkers

by Elizabeth E. Hull, McKale R. Montgomery and Kathryn J. Leyva

Int. J. Mol. Sci. 2017, 18(7), 1361; https://doi.org/10.3390/ijms18071361 - 26 Jun 2017

Cited by 23 | Viewed by 9059

Abstract

Emerging evidence suggests that the enzymes in the biosynthetic pathway for the synthesis of heparan sulfate moieties of heparan sulfate proteoglycans (HSPGs) are epigenetically regulated at many levels. As the exact composition of the heparan sulfate portion of the resulting HSPG molecules is [...] Read more.

Emerging evidence suggests that the enzymes in the biosynthetic pathway for the synthesis of heparan sulfate moieties of heparan sulfate proteoglycans (HSPGs) are epigenetically regulated at many levels. As the exact composition of the heparan sulfate portion of the resulting HSPG molecules is critical to the broad spectrum of biological processes involved in oncogenesis, the epigenetic regulation of heparan sulfate biosynthesis has far-reaching effects on many cellular activities related to cancer progression. Given the current focus on developing new anti-cancer therapeutics focused on epigenetic targets, it is important to understand the effects that these emerging therapeutics may have on the synthesis of HSPGs as alterations in HSPG composition may have profound and unanticipated effects. As an introduction, this review will briefly summarize the variety of important roles which HSPGs play in a wide-spectrum of cancer-related cellular and physiological functions and then describe the biosynthesis of the heparan sulfate chains of HSPGs, including how alterations observed in cancer cells serve as potential biomarkers. This review will then focus on detailing the multiple levels of epigenetic regulation of the enzymes in the heparan sulfate synthesis pathway with a particular focus on regulation by miRNA and effects of epigenetic therapies on HSPGs. We will also explore the use of lectins to detect differences in heparan sulfate composition and preview their potential diagnostic and prognostic use in the clinic. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Open AccessReview

Genomic Insight into the Role of lncRNAs in Cancer Susceptibility

by Ping Gao and Gong-Hong Wei

Int. J. Mol. Sci. 2017, 18(6), 1239; https://doi.org/10.3390/ijms18061239 - 9 Jun 2017

Cited by 76 | Viewed by 6456

Abstract

With the development of advanced genomic methods, a large amount of long non-coding RNAs (lncRNAs) have been found to be important for cancer initiation and progression. Given that most of the genome-wide association study (GWAS)-identiﬁed cancer risk SNPs are located in the noncoding [...] Read more.

With the development of advanced genomic methods, a large amount of long non-coding RNAs (lncRNAs) have been found to be important for cancer initiation and progression. Given that most of the genome-wide association study (GWAS)-identiﬁed cancer risk SNPs are located in the noncoding region, the expression and function of lncRNAs are more likely to be affected by the SNPs. The SNPs may affect the expression of lncRNAs directly through disrupting the binding of transcription factors or indirectly by affecting the expression of regulatory factors. Moreover, SNPs may disrupt the interaction between lncRNAs and other RNAs orproteins. Unveiling the relationship of lncRNA, protein-coding genes, transcription factors and miRNAs from the angle of genomics will improve the accuracy of disease prediction and help ﬁnd new therapeutic targets. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Association of Smoking, Alcohol Use, and Betel Quid Chewing with Epigenetic Aberrations in Cancers

by Tong-Hong Wang, Shih-Min Hsia, Yin-Hwa Shih and Tzong-Ming Shieh

Int. J. Mol. Sci. 2017, 18(6), 1210; https://doi.org/10.3390/ijms18061210 - 6 Jun 2017

Cited by 47 | Viewed by 7627

Abstract

Numerous environmental factors such as diet, alcohol use, stress, and environmental chemicals are known to elicit epigenetic changes, leading to increased rates of cancers and other diseases. The incidence of head and neck cancer, one of the most common cancers in Taiwanese males, [...] Read more.

Numerous environmental factors such as diet, alcohol use, stress, and environmental chemicals are known to elicit epigenetic changes, leading to increased rates of cancers and other diseases. The incidence of head and neck cancer, one of the most common cancers in Taiwanese males, is increasing: oral cancer and nasopharyngeal carcinoma are ranked fourth and tenth respectively, among the top ten cancers in this group, and a major cause of cancer-related deaths in Taiwanese males. Previous studies have identified smoking, alcohol use, and betel quid chewing as the three major causes of head and neck cancers; these three social habits are commonly observed in Taiwanese males, resulting in an increasing morbidity rate of head and neck cancers in this population. In this literature review, we discuss the association between specific components of betel quid, alcohol, and tobacco, and the occurrence of head and neck cancers, lung cancer, gastrointestinal cancers, and urethral cancer. We focus on regulatory mechanisms at the epigenetic level and their oncogenic effects. The review further discusses the application of FDA-approved epigenetic drugs as therapeutic strategies against cancer. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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EZH2 in Cancer Progression and Potential Application in Cancer Therapy: A Friend or Foe?

by Ke-Sin Yan, Chia-Yuan Lin, Tan-Wei Liao, Cheng-Ming Peng, Shou-Chun Lee, Yi-Jui Liu, Wing P. Chan and Ruey-Hwang Chou

Int. J. Mol. Sci. 2017, 18(6), 1172; https://doi.org/10.3390/ijms18061172 - 31 May 2017

Cited by 76 | Viewed by 8990

Abstract

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) to regulate gene expression through epigenetic machinery. EZH2 functions as a double-facet molecule in regulation of gene expression via repression or activation mechanisms, depending on [...] Read more.

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) to regulate gene expression through epigenetic machinery. EZH2 functions as a double-facet molecule in regulation of gene expression via repression or activation mechanisms, depending on the different cellular contexts. EZH2 interacts with both histone and non-histone proteins to modulate diverse physiological functions including cancer progression and malignancy. In this review article, we focused on the updated information regarding microRNAs (miRNAs) and long non coding RNAs (lncRNAs) in regulation of EZH2, the oncogenic and tumor suppressive roles of EZH2 in cancer progression and malignancy, as well as current pre-clinical and clinical trials of EZH2 inhibitors. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Aberrant DNA Methylation as a Biomarker and a Therapeutic Target of Cholangiocarcinoma

by Toshiaki Nakaoka, Yoshimasa Saito and Hidetsugu Saito

Int. J. Mol. Sci. 2017, 18(6), 1111; https://doi.org/10.3390/ijms18061111 - 23 May 2017

Cited by 47 | Viewed by 8031

Abstract

Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients [...] Read more.

Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients with cholangiocarcinoma is poor. Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability during carcinogenesis. Studies have shown that the tumor suppressor genes and microRNAs (miRNAs) including MLH1, p14, p16, death-associated protein kinase (DAPK), miR-370 and miR-376c are frequently methylated in cholangiocarcinoma. Silencing of these tumor suppressor genes and miRNAs plays critical roles in the initiation and progression of cholangiocarcinoma. In addition, recent studies have demonstrated that DNA methylation inhibitors induce expression of endogenous retroviruses and exert the anti-tumor effect of via an anti-viral immune response. Aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for the diagnosis and treatment of cholangiocarcinoma. Epigenetic therapy with DNA methylation inhibitors holds considerable promise for the treatment of cholangiocarcinoma through the reactivation of tumor suppressor genes and miRNAs as well as the induction of an anti-viral immune response. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Epigenetic Strategies to Boost Cancer Immunotherapies

by Maria J. Barrero

Int. J. Mol. Sci. 2017, 18(6), 1108; https://doi.org/10.3390/ijms18061108 - 23 May 2017

Cited by 32 | Viewed by 7058

Abstract

Recently, immunotherapeutic approaches have shown impressive responses in a subset of cancer patients. However, the rate of success is low and a large percentage of treated patients do not experience clinical benefits. Therefore, additional strategies are needed to improve responses and select responsive [...] Read more.

Recently, immunotherapeutic approaches have shown impressive responses in a subset of cancer patients. However, the rate of success is low and a large percentage of treated patients do not experience clinical benefits. Therefore, additional strategies are needed to improve responses and select responsive patients. Emerging data suggest that epigenetic drugs can improve the responses to immunotherapy. Understanding the mechanisms of resistance to immunotherapy and the epigenetic events that take place during immune evasion is critical to providing a rational combined use of immunotherapies and epigenetic drugs. This review focuses in the epigenetic mechanisms involved in the responses to immunotherapy and how current drugs that target epigenetic regulators impact on them. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Open AccessReview

Exploiting Epigenetic Alterations in Prostate Cancer

by Simon J. Baumgart and Bernard Haendler

Int. J. Mol. Sci. 2017, 18(5), 1017; https://doi.org/10.3390/ijms18051017 - 9 May 2017

Cited by 27 | Viewed by 7372

Abstract

Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity [...] Read more.

Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity of enzymes and reader proteins involved in these epigenetic processes, leading to the search for dedicated inhibitory compounds. In the wake of encouraging anti-tumor efficacy results in preclinical models, epigenetic modulators addressing different targets are now being tested in prostate cancer patients. In addition, the assessment of microRNAs as stratification biomarkers, and early clinical trials evaluating suppressor microRNAs as potential prostate cancer treatment are being discussed. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Epigenetic Bases of Aberrant Glycosylation in Cancer

by Fabio Dall’Olio and Marco Trinchera

Int. J. Mol. Sci. 2017, 18(5), 998; https://doi.org/10.3390/ijms18050998 - 6 May 2017

Cited by 34 | Viewed by 7310

Abstract

In this review, the sugar portions of glycoproteins, glycolipids, and glycosaminoglycans constitute the glycome, and the genes involved in their biosynthesis, degradation, transport and recognition are referred to as “glycogenes”. The extreme complexity of the glycome requires the regulatory layer to be provided [...] Read more.

In this review, the sugar portions of glycoproteins, glycolipids, and glycosaminoglycans constitute the glycome, and the genes involved in their biosynthesis, degradation, transport and recognition are referred to as “glycogenes”. The extreme complexity of the glycome requires the regulatory layer to be provided by the epigenetic mechanisms. Almost all types of cancers present glycosylation aberrations, giving rise to phenotypic changes and to the expression of tumor markers. In this review, we discuss how cancer-associated alterations of promoter methylation, histone methylation/acetylation, and miRNAs determine glycomic changes associated with the malignant phenotype. Usually, increased promoter methylation and miRNA expression induce glycogene silencing. However, treatment with demethylating agents sometimes results in silencing, rather than in a reactivation of glycogenes, suggesting the involvement of distant methylation-dependent regulatory elements. From a therapeutic perspective aimed at the normalization of the malignant glycome, it appears that miRNA targeting of cancer-deranged glycogenes can be a more specific and promising approach than the use of drugs, which broad target methylation/acetylation. A very specific type of glycosylation, the addition of GlcNAc to serine or threonine (O-GlcNAc), is not only regulated by epigenetic mechanisms, but is an epigenetic modifier of histones and transcription factors. Thus, glycosylation is both under the control of epigenetic mechanisms and is an integral part of the epigenetic code. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Transposable Elements in Human Cancer: Causes and Consequences of Deregulation

by Sumadi Lukman Anwar, Wahyu Wulaningsih and Ulrich Lehmann

Int. J. Mol. Sci. 2017, 18(5), 974; https://doi.org/10.3390/ijms18050974 - 4 May 2017

Cited by 109 | Viewed by 12782

Abstract

Transposable elements (TEs) comprise nearly half of the human genome and play an essential role in the maintenance of genomic stability, chromosomal architecture, and transcriptional regulation. TEs are repetitive sequences consisting of RNA transposons, DNA transposons, and endogenous retroviruses that can invade the [...] Read more.

Transposable elements (TEs) comprise nearly half of the human genome and play an essential role in the maintenance of genomic stability, chromosomal architecture, and transcriptional regulation. TEs are repetitive sequences consisting of RNA transposons, DNA transposons, and endogenous retroviruses that can invade the human genome with a substantial contribution in human evolution and genomic diversity. TEs are therefore firmly regulated from early embryonic development and during the entire course of human life by epigenetic mechanisms, in particular DNA methylation and histone modifications. The deregulation of TEs has been reported in some developmental diseases, as well as for different types of human cancers. To date, the role of TEs, the mechanisms underlying TE reactivation, and the interplay with DNA methylation in human cancers remain largely unexplained. We reviewed the loss of epigenetic regulation and subsequent genomic instability, chromosomal aberrations, transcriptional deregulation, oncogenic activation, and aberrations of non-coding RNAs as the potential mechanisms underlying TE deregulation in human cancers. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Epigenetic Alterations in Parathyroid Cancers

by Chiara Verdelli and Sabrina Corbetta

Int. J. Mol. Sci. 2017, 18(2), 310; https://doi.org/10.3390/ijms18020310 - 1 Feb 2017

Cited by 27 | Viewed by 5599

Abstract

Parathyroid cancers (PCas) are rare malignancies representing approximately 0.005% of all cancers. PCas are a rare cause of primary hyperparathyroidism, which is the third most common endocrine disease, mainly related to parathyroid benign tumors. About 90% of PCas are hormonally active hypersecreting parathormone [...] Read more.

Parathyroid cancers (PCas) are rare malignancies representing approximately 0.005% of all cancers. PCas are a rare cause of primary hyperparathyroidism, which is the third most common endocrine disease, mainly related to parathyroid benign tumors. About 90% of PCas are hormonally active hypersecreting parathormone (PTH); consequently patients present with complications of severe hypercalcemia. Pre-operative diagnosis is often difficult due to clinical features shared with benign parathyroid lesions. Surgery provides the current best chance of cure, though persistent or recurrent disease occurs in about 50% of patients with PCas. Somatic inactivating mutations of CDC73/HRPT2 gene, encoding parafibromin, are the most frequent genetic anomalies occurring in PCas. Recently, the aberrant DNA methylation signature and microRNA expression profile have been identified in PCas, providing evidence that parathyroid malignancies are distinct entities from parathyroid benign lesions, showing an epigenetic signature resembling some embryonic aspects. The present paper reviews data about epigenetic alterations in PCas, up to now limited to DNA methylation, chromatin regulators and microRNA profile. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Functions and Epigenetic Regulation of Wwox in Bone Metastasis from Breast Carcinoma: Comparison with Primary Tumors

by Paola Maroni, Emanuela Matteucci, Paola Bendinelli and Maria Alfonsina Desiderio

Int. J. Mol. Sci. 2017, 18(1), 75; https://doi.org/10.3390/ijms18010075 - 1 Jan 2017

Cited by 16 | Viewed by 6878

Abstract

Epigenetic mechanisms influence molecular patterns important for the bone-metastatic process, and here we highlight the role of WW-domain containing oxidoreductase (Wwox). The tumor-suppressor Wwox lacks in almost all cancer types; the variable expression in osteosarcomas is related to lung-metastasis formation, and exogenous Wwox [...] Read more.

Epigenetic mechanisms influence molecular patterns important for the bone-metastatic process, and here we highlight the role of WW-domain containing oxidoreductase (Wwox). The tumor-suppressor Wwox lacks in almost all cancer types; the variable expression in osteosarcomas is related to lung-metastasis formation, and exogenous Wwox destabilizes HIF-1α (subunit of Hypoxia inducible Factor-1, HIF-1) affecting aerobic glycolysis. Our recent studies show critical functions of Wwox present in 1833-osteotropic clone, in the corresponding xenograft model, and in human bone metastasis from breast carcinoma. In hypoxic-bone metastatic cells, Wwox enhances HIF-1α stabilization, phosphorylation, and nuclear translocation. Consistently, in bone-metastasis specimens Wwox localizes in cytosolic/perinuclear area, while TAZ (transcriptional co-activator with PDZ-binding motif) and HIF-1α co-localize in nuclei, playing specific regulatory mechanisms: TAZ is a co-factor of HIF-1, and Wwox regulates HIF-1 activity by controlling HIF-1α. In vitro, DNA methylation affects Wwox-protein synthesis; hypoxia decreases Wwox-protein level; hepatocyte growth factor (HGF) phosphorylates Wwox driving its nuclear shuttle, and counteracting a Twist program important for the epithelial phenotype and metastasis colonization. In agreement, in 1833-xenograft mice under DNA-methyltransferase blockade with decitabine, Wwox increases in nuclei/cytosol counteracting bone metastasis with prolongation of the survival. However, Wwox seems relevant for the autophagic process which sustains metastasis, enhancing more Beclin-1 than p62 protein levels, and p62 accumulates under decitabine consistent with adaptability of metastasis to therapy. In conclusion, Wwox methylation as a bone-metastasis therapeutic target would depend on autophagy conditions, and epigenetic mechanisms regulating Wwox may influence the phenotype of bone metastasis. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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