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Cancer Epigenetics 2018

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 October 2018) | Viewed by 20026

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Prof. Dr. Nicoletta Sacchi

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Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Interests: genome wide epigenetic control of transcription; transcription factors and nuclear receptors; regulatory RNAs
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Dear Colleagues,

Epigenetic mechanisms, recognized for playing a fundamental role in human development, play a relevant role in the initiation and progression of cancer. In the prenatal period, and throughout the lifetime, our genome is influenced by both the intrinsic genetic environment and a multitude of factors of the external environment. The many different epigenetic mechanisms that govern normal developmental processes—in space and time, when go awry—not only trigger cancer initiation and drive cancer progression, but also confer resistance to physiological signals, which are naturally meant to deter and protect our cells from becoming cancer cells.

Developmental processes and cancer are intimately linked. Thus, the focus of this second “Cancer Epigenetics” Special Issue of the International Journal of Molecular Sciences (IJMS) is on molecular cell mechanisms connecting normal development and cancer, with emphasis on the interplay of diverse epigenetic components, including chromatin modifiers and the multitude of regulatory noncoding RNAs. To this end, we welcome provocative commentaries, reviews and challenging research articles on the “epigenetic basis of cancer”.

Looking forward to new submissions coming from all over the world.

Sincerely,

Prof. Dr. Nicoletta Sacchi
Guest Editor

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Keywords

DNA hypomethylation and hypermethylation
histone modifications
chromatin modifying enzymes
epigenetic regulation of transcription
non-coding RNAs
epigenetic diagnostics
epigenetic therapy
epigenomics
epitranscriptomics

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Published Papers (4 papers)

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Research

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23 pages, 2944 KiB

Open AccessArticle

Novel Clofarabine-Based Combinations with Polyphenols Epigenetically Reactivate Retinoic Acid Receptor Beta, Inhibit Cell Growth, and Induce Apoptosis of Breast Cancer Cells

by Katarzyna Lubecka, Agnieszka Kaufman-Szymczyk, Barbara Cebula-Obrzut, Piotr Smolewski, Janusz Szemraj and Krystyna Fabianowska-Majewska

Int. J. Mol. Sci. 2018, 19(12), 3970; https://doi.org/10.3390/ijms19123970 - 10 Dec 2018

Cited by 22 | Viewed by 4228

Abstract

An epigenetic component, especially aberrant DNA methylation pattern, has been shown to be frequently involved in sporadic breast cancer development. A growing body of literature demonstrates that combination of agents, i.e. nucleoside analogues with dietary phytochemicals, may provide enhanced therapeutic effects in epigenetic reprogramming of cancer cells. Clofarabine (2-chloro-2′-fluoro-2′-deoxyarabinosyladenine, ClF), a second-generation 2′-deoxyadenosine analogue, has numerous anti-cancer effects, including potential capacity to regulate epigenetic processes. Our present study is the first to investigate the combinatorial effects of ClF (used at IC₅₀ concentration) with epigallocatechin-3-gallate (EGCG, tea catechin) or genistein (soy phytoestrogen), at physiological concentrations, on breast cancer cell growth, apoptosis, and epigenetic regulation of retinoic acid receptor beta (RARB) transcriptional activity. In MCF7 and MDA-MB-231 cells, RARB promoter methylation and expression of RARB, modifiers of DNA methylation reaction (DNMT1, CDKN1A, TP53), and potential regulator of RARB transcription, PTEN, were estimated using methylation-sensitive restriction analysis (MSRA) and quantitative real-time polymerase chain reaction (qPCR), respectively. The combinatorial exposures synergistically or additively inhibited the growth and induced apoptosis of breast cancer cells, followed by RARB hypomethylation with concomitant multiple increase in RARB, PTEN, and CDKN1A transcript levels. Taken together, our results demonstrate the ability of ClF-based combinations with polyphenols to promote cancer cell death and reactivate DNA methylation-silenced tumor suppressor genes in breast cancer cells with different invasive potential. Full article

(This article belongs to the Special Issue Cancer Epigenetics 2018)

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13 pages, 2698 KiB

Open AccessArticle

Aberrant Epigenetic Regulation in Head and Neck Cancer Due to Distinct EZH2 Overexpression and DNA Hypermethylation

by Daiki Mochizuki, Yuki Misawa, Hideya Kawasaki, Atsushi Imai, Shiori Endo, Masato Mima, Satoshi Yamada, Takuya Nakagawa, Takeharu Kanazawa and Kiyoshi Misawa

Int. J. Mol. Sci. 2018, 19(12), 3707; https://doi.org/10.3390/ijms19123707 - 22 Nov 2018

Cited by 24 | Viewed by 4142

Abstract

Enhancer of Zeste homologue 2 (EZH2) overexpression is associated with tumor proliferation, metastasis, and poor prognosis. Targeting and inhibition of EZH2 is a potentially effective therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). We analyzed EZH2 mRNA expression in a well-characterized dataset of 230 (110 original and 120 validation cohorts) human head and neck cancer samples. This study aimed to investigate the effects of inhibiting EZH2, either via RNA interference or via pharmacotherapy, on HNSCC growth. EZH2 upregulation was significantly correlated with recurrence (p < 0.001) and the methylation index of tumor suppressor genes (p < 0.05). DNMT3A was significantly upregulated upon EZH2 upregulation (p = 0.043). Univariate analysis revealed that EZH2 upregulation was associated with poor disease-free survival (log-rank test, p < 0.001). In multivariate analysis, EZH2 upregulation was evaluated as a significant independent prognostic factor of disease-free survival (hazard ratio: 2.085, 95% confidence interval: 1.390–3.127; p < 0.001). Cells treated with RNA interference and DZNep, an EZH2 inhibitor, showed the most dramatic changes in expression, accompanied with a reduction in the growth and survival of FaDu cells. These findings suggest that EZH2 upregulation is correlated with tumor aggressiveness and adverse patient outcomes in HNSCC. Evaluation of EZH2 expression might help predict the prognosis of HNSCC patients. Full article

(This article belongs to the Special Issue Cancer Epigenetics 2018)

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14 pages, 4689 KiB

Open AccessArticle

Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations

by Jeffrey A. Thompson, Brock C. Christensen and Carmen J. Marsit

Int. J. Mol. Sci. 2018, 19(8), 2296; https://doi.org/10.3390/ijms19082296 - 5 Aug 2018

Cited by 8 | Viewed by 3551

Abstract

Bidirectional gene promoters affect the transcription of two genes, leading to the hypothesis that they should exhibit protection against genetic or epigenetic changes in cancer. Therefore, they provide an excellent opportunity to learn about promoter susceptibility to somatic alteration in tumors. We tested this hypothesis using data from genome-scale DNA methylation (14 cancer types), simple somatic mutation (10 cancer types), and copy number variation profiling (14 cancer types). For DNA methylation, the difference in rank differential methylation between tumor and tumor-adjacent normal matched samples based on promoter type was tested by the Wilcoxon rank sum test. Logistic regression was used to compare differences in simple somatic mutations. For copy number alteration, a mixed effects logistic regression model was used. The change in methylation between non-diseased tissues and their tumor counterparts was significantly greater in single compared to bidirectional promoters across all 14 cancer types examined. Similarly, the extent of copy number alteration was greater in single gene compared to bidirectional promoters for all 14 cancer types. Furthermore, among 10 cancer types with available simple somatic mutation data, bidirectional promoters were slightly more susceptible. These results suggest that selective pressures related with specific functional impacts during carcinogenesis drive the susceptibility of promoter regions to somatic alteration. Full article

(This article belongs to the Special Issue Cancer Epigenetics 2018)

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Review

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35 pages, 794 KiB

Open AccessReview

Epigenetic Targeting of Autophagy via HDAC Inhibition in Tumor Cells: Role of p53

by Maria Mrakovcic, Lauren Bohner, Marcel Hanisch and Leopold F. Fröhlich

Int. J. Mol. Sci. 2018, 19(12), 3952; https://doi.org/10.3390/ijms19123952 - 8 Dec 2018

Cited by 43 | Viewed by 7506

Abstract

Tumor development and progression is the consequence of genetic as well as epigenetic alterations of the cell. As part of the epigenetic regulatory system, histone acetyltransferases (HATs) and deacetylases (HDACs) drive the modification of histone as well as non-histone proteins. Derailed acetylation-mediated gene expression in cancer due to a delicate imbalance in HDAC expression can be reversed by histone deacetylase inhibitors (HDACi). Histone deacetylase inhibitors have far-reaching anticancer activities that include the induction of cell cycle arrest, the inhibition of angiogenesis, immunomodulatory responses, the inhibition of stress responses, increased generation of oxidative stress, activation of apoptosis, autophagy eliciting cell death, and even the regulation of non-coding RNA expression in malignant tumor cells. However, it remains an ongoing issue how tumor cells determine to respond to HDACi treatment by preferentially undergoing apoptosis or autophagy. In this review, we summarize HDACi-mediated mechanisms of action, particularly with respect to the induction of cell death. There is a keen interest in assessing suitable molecular factors allowing a prognosis of HDACi-mediated treatment. Addressing the results of our recent study, we highlight the role of p53 as a molecular switch driving HDACi-mediated cellular responses towards one of both types of cell death. These findings underline the importance to determine the mutational status of p53 for an effective outcome in HDACi-mediated tumor therapy. Full article

(This article belongs to the Special Issue Cancer Epigenetics 2018)

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