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DNA Methylation and Its Application in Cancer Therapy
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DNA Methylation and Its Application in Cancer Therapy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 61727

Special Issue Editors

Prof. Dr. Gerda Egger

E-Mail Website
Guest Editor
1. Department of Pathology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
2. Ludwig Boltzmann Institute Applied Diagnostics, Währinger Gürtel 18-20, 1090 Vienna, Austria
Interests: epigenetics; epigenomics; DNA methylation; chromatin; histone modification; tumor biology; biomarker
Special Issues, Collections and Topics in MDPI journals
Dr. Sabine Lagger

E-Mail Website
Guest Editor
Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Veterinärplatz 1, A-1210 Vienna, Austria
Interests: epigenetics; DNA methylation; chromatin; development; epigenomics

Special Issue Information

Dear Colleagues,

DNA methylation was one of the first identified epigenetic modifications and its role for development, genome stability, and cellular memory have been well established. Recent studies have implicated aberrant DNA methylation and mutations of DNA methyltransferases in a variety of disorders, including cancer. Especially hypermethylation of CpG islands and genome-wide hypomethylation are hallmarks of cancer cells. Although clear mechanistic evidence remains elusive, epigenetic drugs have successfully entered the clinics for the treatment of hematopoietic cancers, and several clinical studies are ongoing testing their efficacy for solid tumors. In addition, epigenetic biomarkers have attracted clinical interest as prognostic and predictive tools for patient management. Notably, non-invasive liquid biopsies represent an exciting opportunity to develop specific and sensitive personalized diagnostics for dynamic patient monitoring and stratification.

This Special Issue aims to highlight the current knowledge on relevant DNA methylation-based mechanisms of tumorigenesis as well as latest advances in epigenetic therapy and biomarker development and welcomes both review and original research articles.

Prof. Dr. Gerda Egger
Dr. Sabine Lagger
Guest Editors

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Keywords

  • DNA methylation
  • epigenomics
  • epigenetic therapy
  • epigenetic biomarkers

Published Papers (13 papers)

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Research

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18 pages, 5309 KiB  
Article
An Evolutionary Cancer Epigenetic Approach Revealed DNA Hypermethylation of Ultra-Conserved Non-Coding Elements in Squamous Cell Carcinoma of Different Mammalian Species
by Luca Morandi, Silvia Sabattini, Andrea Renzi, Antonella Rigillo, Giuliano Bettini, Eva Dervas, Alexandria Schauer, Marco Morandi, Davide B. Gissi, Achille Tarsitano, Stefania Evangelisti and Caterina Tonon
Cells 2020, 9(9), 2092; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9092092 - 13 Sep 2020
Cited by 3 | Viewed by 2221
Abstract
Background: Ultra-conserved non-coding elements (UCNEs) are genomic sequences that exhibit > 95% sequence identity between humans, mammals, birds, reptiles, and fish. Recent findings reported their functional role in cancer. The aim of this study was to evaluate the DNA methylation modifications of UNCEs [...] Read more.
Background: Ultra-conserved non-coding elements (UCNEs) are genomic sequences that exhibit > 95% sequence identity between humans, mammals, birds, reptiles, and fish. Recent findings reported their functional role in cancer. The aim of this study was to evaluate the DNA methylation modifications of UNCEs in squamous cell carcinoma (SCC) from different mammal species. Methods: Fifty SCCs from 26 humans, 17 cats, 3 dogs, 1 horse, 1 bovine, 1 badger, and 1 porcupine were investigated. Fourteen feline stomatitis and normal samples from 36 healthy human donors, 7 cats, 5 dogs, 5 horses, 2 bovines and 1 badger were collected as normal controls. Bisulfite next generation sequencing evaluated the DNA methylation level from seven UCNEs (uc.160, uc.283, uc.416, uc.339, uc.270, uc.299, and uc.328). Results: 57/59 CpGs were significantly different according to the Kruskal–Wallis test (p < 0.05) comparing normal samples with SCC. A common DNA hypermethylation pattern was observed in SCCs from all the species evaluated in this study, with an increasing trend of hypermethylation starting from normal mucosa, through stomatitis to SCC. Conclusions: Our findings indicate that UCNEs are hypermethylated in human SCC, and this behavior is also conserved among different species of mammals. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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18 pages, 4225 KiB  
Article
S-Adenosylmethionine Treatment of Colorectal Cancer Cell Lines Alters DNA Methylation, DNA Repair and Tumor Progression-Related Gene Expression
by Sára Zsigrai, Alexandra Kalmár, Zsófia B. Nagy, Barbara K. Barták, Gábor Valcz, Krisztina A. Szigeti, Orsolya Galamb, Titanilla Dankó, Anna Sebestyén, Gábor Barna, Vanessza Szabó, Orsolya Pipek, Anna Medgyes-Horváth, István Csabai, Zsolt Tulassay, Péter Igaz, István Takács and Béla Molnár
Cells 2020, 9(8), 1864; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9081864 - 09 Aug 2020
Cited by 16 | Viewed by 4155
Abstract
Global DNA hypomethylation is a characteristic feature of colorectal carcinoma (CRC). The tumor inhibitory effect of S-adenosylmethionine (SAM) methyl donor has been described in certain cancers including CRC. However, the molecular impact of SAM treatment on CRC cell lines with distinct genetic features [...] Read more.
Global DNA hypomethylation is a characteristic feature of colorectal carcinoma (CRC). The tumor inhibitory effect of S-adenosylmethionine (SAM) methyl donor has been described in certain cancers including CRC. However, the molecular impact of SAM treatment on CRC cell lines with distinct genetic features has not been evaluated comprehensively. HT-29 and SW480 cells were treated with 0.5 and 1 mmol/L SAM for 48 h followed by cell proliferation measurements, whole-genome transcriptome and methylome analyses, DNA stability assessments and exome sequencing. SAM reduced cell number and increased senescence by causing S phase arrest, besides, multiple EMT-related genes (e.g., TGFB1) were downregulated in both cell lines. Alteration in the global DNA methylation level was not observed, but certain methylation changes in gene promoters were detected. SAM-induced γ-H2AX elevation could be associated with activated DNA repair pathway showing upregulated gene expression (e.g., HUS1). Remarkable genomic stability elevation, namely, decreased micronucleus number and comet tail length was observed only in SW480 after treatment. SAM has the potential to induce senescence, DNA repair, genome stability and to reduce CRC progression. However, the different therapeutic responses of HT-29 and SW480 to SAM emphasize the importance of the molecular characterization of CRC cases prior to methyl donor supplementation. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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16 pages, 2893 KiB  
Article
Discovery of Molecular DNA Methylation-Based Biomarkers through Genome-Wide Analysis of Response Patterns to BCG for Bladder Cancer
by Dafina Ilijazi, Walter Pulverer, Iris E. Ertl, Ursula Lemberger, Shoji Kimura, Mohammad Abufaraj, David D’Andrea, Benjamin Pradere, Andreas Bruchbacher, Anna Graf, Francesco Soria, Martin Susani, Andrea Haitel, Luca Molinaro, Armin Pycha, Evi Comploj, Stephan Pabinger, Andreas Weinhäusel, Gerda Egger, Shahrokh F. Shariat and Melanie R. Hassleradd Show full author list remove Hide full author list
Cells 2020, 9(8), 1839; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9081839 - 05 Aug 2020
Cited by 11 | Viewed by 3871
Abstract
Background: Bacillus Calmette-Guérin (BCG) immunotherapy, the standard adjuvant intravesical therapy for some intermediate and most high-risk non-muscle invasive bladder cancers (NMIBCs), suffers from a heterogenous response rate. Molecular markers to help guide responses are scarce and currently not used in the clinical setting. [...] Read more.
Background: Bacillus Calmette-Guérin (BCG) immunotherapy, the standard adjuvant intravesical therapy for some intermediate and most high-risk non-muscle invasive bladder cancers (NMIBCs), suffers from a heterogenous response rate. Molecular markers to help guide responses are scarce and currently not used in the clinical setting. Methods: To identify novel biomarkers and pathways involved in response to BCG immunotherapy, we performed a genome-wide DNA methylation analysis of NMIBCs before BCG therapy. Genome-wide DNA methylation profiles of DNA isolated from tumors of 26 BCG responders and 27 failures were obtained using the Infinium MethylationEPIC BeadChip. Results: Distinct DNA methylation patterns were found by genome-wide analysis in the two groups. Differentially methylated CpG sites were predominantly located in gene promoters and gene bodies associated with bacterial invasion of epithelial cells, chemokine signaling, endocytosis, and focal adhesion. In total, 40 genomic regions with a significant difference in methylation between responders and failures were detected. The differential methylation state of six of these regions, localized in the promoters of the genes GPR158, KLF8, C12orf42, WDR44, FLT1, and CHST11, were internally validated by bisulfite-sequencing. GPR158 promoter hypermethylation was the best predictor of BCG failure with an AUC of 0.809 (p-value < 0.001). Conclusions: Tumors from BCG responders and BCG failures harbor distinct DNA methylation profiles. Differentially methylated DNA regions were detected in genes related to pathways involved in bacterial invasion of cells or focal adhesion. We identified candidate DNA methylation biomarkers that may help to predict patient prognosis after external validation in larger, well-designed cohorts. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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22 pages, 6408 KiB  
Article
Potential Prognostic Role of SPARC Methylation in Non-Small-Cell Lung Cancer
by Federico Pio Fabrizio, Angelo Sparaneo, Andrea Fontana, Tommaso Mazza, Paolo Graziano, Angela Pantalone, Paola Parente, Flavia Centra, Natalizia Orlando, Domenico Trombetta, Annamaria la Torre, Gian Maria Ferretti, Marco Taurchini, Concetta Martina Di Micco, Evaristo Maiello, Vito Michele Fazio, Antonio Rossi and Lucia Anna Muscarella
Cells 2020, 9(6), 1523; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9061523 - 22 Jun 2020
Cited by 10 | Viewed by 2648
Abstract
The silencing of SPARC (secreted protein acid and rich in cysteine) gene through methylation of its promoter region represents a common event in many solid tumors and it is frequently associated with tumor progression and an aggressive clinical outcome. Anyhow, the data concerning [...] Read more.
The silencing of SPARC (secreted protein acid and rich in cysteine) gene through methylation of its promoter region represents a common event in many solid tumors and it is frequently associated with tumor progression and an aggressive clinical outcome. Anyhow, the data concerning the epigenetic mechanism of SPARC deregulation and its prognostic value in lung cancer are still incomplete. We explored the aberrant methylation of SPARC and its effects in 4 non-small cell lung cancer (NSCLC) cell lines and 59 NSCLC tissues and correlated the methylation levels with clinical-pathological features and disease outcome of patients. In 3 out of 4 tumor cell lines high SPARC methylation levels were observed. An inverse correlation between the epigenetic silencing and SPARC expression was confirmed by 5-Aza-2′-deoxycytidine ((5-Aza-CdR) treatment that also significantly induced a reduction in cell viability, proliferation and tumor cell migration. In tissues, the DNA methylation levels of the SPARC gene were significantly lower in paired non-neoplastic lungs (NLs) and normal lungs distant from tumor (NLDTs) than in NSCLCs (p = 0.002 and p = 0.0034 respectively). A promoter hypermethylation was detected in 68% of squamous cell carcinoma (SqCCs, 17/25) and 56% of adenocarcinoma (ADCs, 19/34), with SqCC showing the highest levels of methylation. Higher SPARC methylation levels were significantly associated with higher mortality risk both in all NSCLCs early stage patients (Hazard Ratio, HR = 1.97; 95% Confidence Interval, CI: 1.32–2.93; p = 0.001) and in those with SqCC (HR = 2.96; 95% CI: 1.43–6.12; p = 0.003). Promoter methylation of SPARC gene should represent an interesting prognostic biomarker in NSCLC, with potential application in the squamous early-stage context. Further research in this setting on larger independent cohorts of lung patients with different histologies and stages of disease are warranted. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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17 pages, 1720 KiB  
Article
Epigenetic Analysis of Circulating Tumor DNA in Localized and Metastatic Prostate Cancer: Evaluation of Clinical Biomarker Potential
by Marianne Trier Bjerre, Maibritt Nørgaard, Ole Halfdan Larsen, Sarah Østrup Jensen, Siri H. Strand, Peter Østergren, Mikkel Fode, Jacob Fredsøe, Benedicte Parm Ulhøi, Martin Mørck Mortensen, Jørgen Bjerggaard Jensen, Michael Borre and Karina D. Sørensen
Cells 2020, 9(6), 1362; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9061362 - 31 May 2020
Cited by 17 | Viewed by 3821
Abstract
Novel and minimally-invasive prostate cancer (PCa)-specific biomarkers are needed to improve diagnosis and risk stratification. Here, we investigated the biomarker potential in localized and de novo metastatic PCa (mPCa) of methylated circulating tumor DNA (ctDNA) in plasma. Using the Marmal-aid database and in-house [...] Read more.
Novel and minimally-invasive prostate cancer (PCa)-specific biomarkers are needed to improve diagnosis and risk stratification. Here, we investigated the biomarker potential in localized and de novo metastatic PCa (mPCa) of methylated circulating tumor DNA (ctDNA) in plasma. Using the Marmal-aid database and in-house datasets, we identified three top candidates specifically hypermethylated in PCa tissue: DOCK2, HAPLN3, and FBXO30 (specificity/sensitivity: 80%–100%/75–94%). These candidates were further analyzed in plasma samples from 36 healthy controls, 61 benign prostatic hyperplasia (BPH), 102 localized PCa, and 65 de novo mPCa patients using methylation-specific droplet digital PCR. Methylated ctDNA for DOCK2/HAPLN3/FBXO30 was generally not detected in healthy controls, BPH patients, nor in patients with localized PCa despite a positive signal in 98%–100% of matched radical prostatectomy tissue samples. However, ctDNA methylation of DOCK2, HAPLN3, and/or FBXO30 was detected in 61.5% (40/65) of de novo mPCa patients and markedly increased in high- compared to low-volume mPCa (89.3% (25/28) vs. 32.1% (10/31), p < 0.001). Moreover, detection of methylated ctDNA was associated with significantly shorter time to progression to metastatic castration resistant PCa, independent of tumor-volume. These results indicate that methylated ctDNA (DOCK2/HAPLN3/FBXO30) may be potentially useful for identification of hormone-naïve mPCa patients who could benefit from intensified treatment. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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Review

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35 pages, 1098 KiB  
Review
Aberrant DNA Methylation of ABC Transporters in Cancer
by Katja Zappe and Margit Cichna-Markl
Cells 2020, 9(10), 2281; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102281 - 13 Oct 2020
Cited by 24 | Viewed by 3240
Abstract
ATP-binding cassette (ABC) transporters play a crucial role in multidrug resistance (MDR) of cancers. They function as efflux pumps, resulting in limited effectiveness or even failure of therapy. Increasing evidence suggests that ABC transporters are also involved in tumor initiation, progression, and metastasis. [...] Read more.
ATP-binding cassette (ABC) transporters play a crucial role in multidrug resistance (MDR) of cancers. They function as efflux pumps, resulting in limited effectiveness or even failure of therapy. Increasing evidence suggests that ABC transporters are also involved in tumor initiation, progression, and metastasis. Tumors frequently show multiple genetic and epigenetic abnormalities, including changes in histone modification and DNA methylation. Alterations in the DNA methylation status of ABC transporters have been reported for a variety of cancer types. In this review, we outline the current knowledge of DNA methylation of ABC transporters in cancer. We give a brief introduction to structure, function, and gene regulation of ABC transporters that have already been investigated for their DNA methylation status in cancer. After giving an overview of the applied methodologies and the CpGs analyzed, we summarize and discuss the findings on aberrant DNA methylation of ABC transporters by cancer types. We conclude our review with the discussion of the potential to target aberrant DNA methylation of ABC transporters for cancer therapy. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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19 pages, 1205 KiB  
Review
Aberrant Methylation of LINE-1 Transposable Elements: A Search for Cancer Biomarkers
by Anastasia A. Ponomaryova, Elena Y. Rykova, Polina A. Gervas, Nadezhda V. Cherdyntseva, Ilgar Z. Mamedov and Tatyana L. Azhikina
Cells 2020, 9(9), 2017; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9092017 - 02 Sep 2020
Cited by 30 | Viewed by 5838
Abstract
Cancer remains one of the main causes of human mortality despite significant progress in its diagnostics and therapy achieved in the past decade. Massive hypomethylation of retrotransposons, in particular LINE-1, is considered a hallmark of most malignant transformations as it results in the [...] Read more.
Cancer remains one of the main causes of human mortality despite significant progress in its diagnostics and therapy achieved in the past decade. Massive hypomethylation of retrotransposons, in particular LINE-1, is considered a hallmark of most malignant transformations as it results in the reactivation of retroelements and subsequent genomic instability. Accumulating data on LINE-1 aberrant methylation in different tumor types indicates its significant role in cancer initiation and progression. However, direct evidence that LINE-1 activation can be used as a cancer biomarker is still limited. The objective of this review was to critically evaluate the published results regarding the diagnostic/prognostic potential of the LINE-1 methylation status in cancer. Our analysis indicates that LINE-1 hypomethylation is a promising candidate biomarker of cancer development, which, however, needs validation in both clinical and laboratory studies to confirm its applicability to different cancer types and/or stages. As LINE-1 is present in multiple cell-free copies in blood, it has advantages over single-copy genes regarding perspectives of using its methylation status as an epigenetic cancer biomarker for cell-free DNA liquid biopsy. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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36 pages, 2311 KiB  
Review
The Impact of Natural Dietary Compounds and Food-Borne Mycotoxins on DNA Methylation and Cancer
by Terisha Ghazi, Thilona Arumugam, Ashmika Foolchand and Anil A. Chuturgoon
Cells 2020, 9(9), 2004; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9092004 - 31 Aug 2020
Cited by 15 | Viewed by 5778
Abstract
Cancer initiation and progression is an accumulation of genetic and epigenetic modifications. DNA methylation is a common epigenetic modification that regulates gene expression, and aberrant DNA methylation patterns are considered a hallmark of cancer. The human diet is a source of micronutrients, bioactive [...] Read more.
Cancer initiation and progression is an accumulation of genetic and epigenetic modifications. DNA methylation is a common epigenetic modification that regulates gene expression, and aberrant DNA methylation patterns are considered a hallmark of cancer. The human diet is a source of micronutrients, bioactive molecules, and mycotoxins that have the ability to alter DNA methylation patterns and are thus a contributing factor for both the prevention and onset of cancer. Micronutrients such as betaine, choline, folate, and methionine serve as cofactors or methyl donors for one-carbon metabolism and other DNA methylation reactions. Dietary bioactive compounds such as curcumin, epigallocatechin-3-gallate, genistein, quercetin, resveratrol, and sulforaphane reactivate essential tumor suppressor genes by reversing aberrant DNA methylation patterns, and therefore, they have shown potential against various cancers. In contrast, fungi-contaminated agricultural foods are a source of potent mycotoxins that induce carcinogenesis. In this review, we summarize the existing literature on dietary micronutrients, bioactive compounds, and food-borne mycotoxins that affect DNA methylation patterns and identify their potential in the onset and treatment of cancer. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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29 pages, 1522 KiB  
Review
DNA Methylation as a Therapeutic Target for Bladder Cancer
by Sandra P. Nunes, Rui Henrique, Carmen Jerónimo and Jesús M. Paramio
Cells 2020, 9(8), 1850; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9081850 - 07 Aug 2020
Cited by 37 | Viewed by 9763
Abstract
Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted by the current treatment options. Thus, the development of new therapeutic strategies, either alternative or complementary [...] Read more.
Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted by the current treatment options. Thus, the development of new therapeutic strategies, either alternative or complementary to the current ones, is of major importance. The disruption of normal epigenetic mechanisms, namely, DNA methylation, is a known early event in cancer development. Consequently, DNA methyltransferase (DNMT) inhibitors constitute a promising therapeutic target for the treatment of BC. Although these inhibitors, mainly nucleoside analogues such as 5-azacytidine (5-aza) and decitabine (DAC), cause re-expression of tumor suppressor genes, inhibition of tumor cell growth, and increased apoptosis in BC experimental models and clinical trials, they also show important drawbacks that prevent their use as a valuable option for the treatment of BC. However, their combination with chemotherapy and/or immune-checkpoint inhibitors could aid in their implementation in the clinical practice. Here, we provide a comprehensive review of the studies exploring the effects of DNA methylation inhibition using DNMTs inhibitors in BC, from in vitro and in vivo studies to clinical trials. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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20 pages, 1847 KiB  
Review
Methylation in HOX Clusters and Its Applications in Cancer Therapy
by Ana Paço, Simone Aparecida de Bessa Garcia and Renata Freitas
Cells 2020, 9(7), 1613; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9071613 - 03 Jul 2020
Cited by 25 | Viewed by 3733
Abstract
HOX genes are commonly known for their role in embryonic development, defining the positional identity of most structures along the anterior–posterior axis. In postembryonic life, HOX gene aberrant expression can affect several processes involved in tumorigenesis such as proliferation, apoptosis, migration and invasion. [...] Read more.
HOX genes are commonly known for their role in embryonic development, defining the positional identity of most structures along the anterior–posterior axis. In postembryonic life, HOX gene aberrant expression can affect several processes involved in tumorigenesis such as proliferation, apoptosis, migration and invasion. Epigenetic modifications are implicated in gene expression deregulation, and it is accepted that methylation events affecting HOX gene expression play crucial roles in tumorigenesis. In fact, specific methylation profiles in the HOX gene sequence or in HOX-associated histones are recognized as potential biomarkers in several cancers, helping in the prediction of disease outcomes and adding information for decisions regarding the patient’s treatment. The methylation of some HOX genes can be associated with chemotherapy resistance, and its identification may suggest the use of other treatment options. The use of epigenetic drugs affecting generalized or specific DNA methylation profiles, an approach that now deserves much attention, seems likely to be a promising weapon in cancer therapy in the near future. In this review, we summarize these topics, focusing particularly on how the regulation of epigenetic processes may be used in cancer therapy. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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31 pages, 1368 KiB  
Review
Methylation-Based Therapies for Colorectal Cancer
by Klara Cervena, Anna Siskova, Tomas Buchler, Pavel Vodicka and Veronika Vymetalkova
Cells 2020, 9(6), 1540; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9061540 - 24 Jun 2020
Cited by 26 | Viewed by 5849
Abstract
Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they [...] Read more.
Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient’s methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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20 pages, 1241 KiB  
Review
DNA Methylation Changes in Human Papillomavirus-Driven Head and Neck Cancers
by Chameera Ekanayake Weeramange, Kai Dun Tang, Sarju Vasani, Julian Langton-Lockton, Liz Kenny and Chamindie Punyadeera
Cells 2020, 9(6), 1359; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9061359 - 31 May 2020
Cited by 27 | Viewed by 4581
Abstract
Disruption of DNA methylation patterns is one of the hallmarks of cancer. Similar to other cancer types, human papillomavirus (HPV)-driven head and neck cancer (HNC) also reveals alterations in its methylation profile. The intrinsic ability of HPV oncoproteins E6 and E7 to interfere [...] Read more.
Disruption of DNA methylation patterns is one of the hallmarks of cancer. Similar to other cancer types, human papillomavirus (HPV)-driven head and neck cancer (HNC) also reveals alterations in its methylation profile. The intrinsic ability of HPV oncoproteins E6 and E7 to interfere with DNA methyltransferase activity contributes to these methylation changes. There are many genes that have been reported to be differentially methylated in HPV-driven HNC. Some of these genes are involved in major cellular pathways, indicating that DNA methylation, at least in certain instances, may contribute to the development and progression of HPV-driven HNC. Furthermore, the HPV genome itself becomes a target of the cellular DNA methylation machinery. Some of these methylation changes appearing in the viral long control region (LCR) may contribute to uncontrolled oncoprotein expression, leading to carcinogenesis. Consistent with these observations, demethylation therapy appears to have significant effects on HPV-driven HNC. This review article comprehensively summarizes DNA methylation changes and their diagnostic and therapeutic indications in HPV-driven HNC. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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22 pages, 1503 KiB  
Review
Epigenetics in Inflammatory Breast Cancer: Biological Features and Therapeutic Perspectives
by Flavia Lima Costa Faldoni, Cláudia Aparecida Rainho and Silvia Regina Rogatto
Cells 2020, 9(5), 1164; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9051164 - 08 May 2020
Cited by 18 | Viewed by 4928
Abstract
Evidence has emerged implicating epigenetic alterations in inflammatory breast cancer (IBC) origin and progression. IBC is a rare and rapidly progressing disease, considered the most aggressive type of breast cancer (BC). At clinical presentation, IBC is characterized by diffuse erythema, skin ridging, dermal [...] Read more.
Evidence has emerged implicating epigenetic alterations in inflammatory breast cancer (IBC) origin and progression. IBC is a rare and rapidly progressing disease, considered the most aggressive type of breast cancer (BC). At clinical presentation, IBC is characterized by diffuse erythema, skin ridging, dermal lymphatic invasion, and peau d’orange aspect. The widespread distribution of the tumor as emboli throughout the breast and intra- and intertumor heterogeneity is associated with its poor prognosis. In this review, we highlighted studies documenting the essential roles of epigenetic mechanisms in remodeling chromatin and modulating gene expression during mammary gland differentiation and the development of IBC. Compiling evidence has emerged implicating epigenetic changes as a common denominator linking the main risk factors (socioeconomic status, environmental exposure to endocrine disruptors, racial disparities, and obesity) with IBC development. DNA methylation changes and their impact on the diagnosis, prognosis, and treatment of IBC are also described. Recent studies are focusing on the use of histone deacetylase inhibitors as promising epigenetic drugs for treating IBC. All efforts must be undertaken to unravel the epigenetic marks that drive this disease and how this knowledge could impact strategies to reduce the risk of IBC development and progression. Full article
(This article belongs to the Special Issue DNA Methylation and Its Application in Cancer Therapy)
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