Aberrant DNA Methylation and Histone Modifications in Cancer


DNA (deoxyribonucleic acid) methylation of cytosines in CpG dinucleotides and post‐translational modifications of histone amino acids are epigenetic mechanisms that are in normal cells involved in specific cell functions, particularly in regulation of transcription and maintenance of stable chromatin. The epigenetic code is highly dynamic and enables the cells to regulate their responses to the intrinsic or environmental signals. Aberrations of DNA methylation patterns and histone modifications are major features observed in all types of cancer. Integrated research of genomic alterations, erroneous gene expression and modifications of epigenomes in cancer cells has revealed the complexity and heterogeneity of this disease. Some of the novel therapeutic and diagnostic approaches based on aberrant promoter hypermethylation and histone modifications, particularly acetylation, have already been translated into a clinical setting, whereas a number of others are being examined in clinical trials.

Key Concepts

  • DNA methylation and histone modifications cooperate in regulation of certain cell functions and responses.
  • Cancer development and progression are characterised by diverse aberrations in epigenetic profiles.
  • Changes in DNA methylation profiles could be used to define specific subsets of cancers, which harbour characteristic genetic alterations.
  • Hypermethylation or hypomethylation of gene promoters, resulting in silencing or activating the gene transcription, respectively, are fundamental in the identification of novel tumour suppressors and oncogenes.
  • Unravelling the functional consequences of methylation signature in nonpromoter regions is complex and will require further research efforts to discern their role in healthy and diseased cells.
  • Epigenetic profiling of cancers has already identified and is still identifying novel targets for the development of therapeutic and diagnostic approaches.

Keywords: biomarker; cancer; CpG island; chromatin; epigenetic therapy; gene silencing; epigenetics; gene expression regulation; histone modifications

Figure 1. Schematic presentation of major DNA methylation and demethylation pathways in mammals. DNA methylation at the carbon‐5 position of cytosine (C, ∼20% of all bases) in the dinucleotide CpG is catalysed by DNMTs to yield 5‐methylcytosine (5mC, ∼1% of all bases and ∼60% of all CpGs) by transferring the methyl group from S‐adenosylmethionine (SAM) to cytosine. TET enzymes are implicated in conversions of 5mC, first by catalysing oxidization of 5mC to 5‐hydroxymethylcytosine (5hmC, ∼0.1% of all bases), followed by formation of 5‐formylcytosine (5fC) and 5‐carboxylcytosine (5caC) (together, oxi‐mC). Through these oxidations, TET proteins mediate active demethylation of methylated CpGs. 5hmC, 5fC and 5caC are repaired via thymine DNA glycosylase (TDG)‐mediated base excision repair (BER) of 5fC:G and 5caC:G base pairs. In addition, replication‐dependent passive demethylation can also occur. Reproduced from Huang and Rao 2014 © Elsevier.
Figure 2. Schematic representation of histone modifications. + Indicates modifications associated with active transcription, − indicates modifications that repress transcription, ac, acetylation; me, methylation; ub, ubiquitination; me1, monomethylation; me2, demethylation; s, symmetric covalent modification.
Figure 3. An example of DNA methylation patterns in normal and cancer cells. (a) For example, in normal cells, most CpGs located outside of promoters in gene bodies and intergenic regions are methylated (red circles), whereas promoter‐associated CpG islands are protected from DNA methylation (white circles). (b) In cancer cells, loss of 5‐methylcytosine occurs at gene bodies and intergenic regions, whereas CpG‐rich regions like promoters are usually heavily methylated, which might lead to transcriptional repression. CpG shores, which have intermediate densities of CpG dinucleotides, are associated with tissue‐specific methylation. In bottom plots, global loss (left plot) and focal gain (right plot) of DNA methylation of two genes, the deleted in colon cancer gene (DCC) and glutathione S‐transferase P1 gene (GTSP1), are presented. Below the gene track are tracks for CpG islands and selected histone modifications, including H3K4me3, which is associated with transcriptionally active promoters, and H3K4me1 and H3K27ac as markers for enhancers. Each colour of the histone tracks represents an individual ENCODE cell line. DCC was taken as an exemplary locus for which long‐range hypomethylation regions (horizontal blue bars) are observed in the breast cancer cell line HCC1954 and in the liver carcinoma cell line HepG2, but not in normal mammary epithelial cells (HMEC) or the myofibroblast cell line IMR90. GTSP1 represents an example of promoter hypermethylation (highlighted in red) in cancer cell lines compared to normal cells. The data was obtained from the University of California Santa Cruz (USCS) genome browser (https://genome.ucsc.edu/). Reproduced with permission form Witte et al. 2014 © BioMed Central.


Auclair G, Guibert S, Bender A and Weber M (2014) Ontogeny of CpG island methylation and specificity of DNMT3 methyltransferases during embryonic development in the mouse. Genome Biology 15 (12): 545.

Barlow DP and Bartolomei MS (2014) Genomic imprinting in mammals. Cold Spring Harbor Perspectives in Biology 6 (2): a018382.

Barsotti AM, Ryskin M, Zhong W, et al. (2015) Epigenetic reprogramming by tumor‐derived EZH2 gain‐of‐function mutations promotes aggressive 3D cell morphologies and enhances melanoma tumor growth. Oncotarget 6 (5): 2928–2938.

Bibikova M, Barnes B, Tsan C, et al. (2011) High density DNA methylation array with single CpG site resolution. Genomics 98 (4): 288–295.

Dang L, White DW, Gross S, et al. (2009) Cancer‐associated IDH1 mutations produce 2‐hydroxyglutarate. Nature 462 (7274): 739–744.

Deaton AM and Bird A (2011) CpG islands and the regulation of transcription. Genes and Development 25 (10): 1010–1022.

Edgar R, Tan PP, Portales‐Casamar E and Pavlidis P (2014) Meta‐analysis of human methylomes reveals stably methylated sequences surrounding CpG islands associated with high gene expression. Epigenetics & Chromatin 7 (1): 28.

Ellis L, Atadja PW and Johnstone RW (2009) Epigenetics in cancer: targeting chromatin modifications. Molecular Cancer Therapeutics 8 (6): 1409–1420.

Figueroa ME, Abdel‐Wahab O, Lu C, et al. (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18 (6): 553–567.

Goossens‐Beumer IJ, Benard A, van Hoesel AQ, et al. (2015) Age‐dependent clinical prognostic value of histone modifications in colorectal cancer. Translational Research 165 (5): 578–588.

Guccione E, Bassi C, Casadio F, et al. (2007) Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive. Nature 449 (7164): 933–937.

Hansen KD, Timp W, Bravo HC, et al. (2011) Increased methylation variation in epigenetic domains across cancer types. Nature Genetics 43 (8): 768–775.

Heyn H, Vidal E, Ferreira HJ, et al. (2016) Epigenomic analysis detects aberrant super‐enhancer DNA methylation in human cancer. Genome Biology 17 (1): 11.

Huang Y and Rao A (2014) Connections between TET proteins and aberrant DNA modification in cancer. Trends in Genetics 30 (10): 464–474.

Iaccarino C, Orlandi E, Ruggeri F, et al. (2015) Prognostic value of MGMT promoter status in non‐resectable glioblastoma after adjuvant therapy. Clinical Neurology and Neurosurgery 132: 1–8.

Ilse P, Biesterfeld S, Pomjanski N, Wrobel C and Schramm M (2014) Analysis of SHOX2 methylation as an aid to cytology in lung cancer diagnosis. Cancer Genomics Proteomics 11 (5): 251–258.

Ioshikhes IP and Zhang MQ (2000) Large‐scale human promoter mapping using CpG islands. Nature Genetics 26 (1): 61–63.

Irizarry RA, Ladd‐Acosta C, Wen B, et al. (2009) The human colon cancer methylome shows similar hypo‐ and hypermethylation at conserved tissue‐specific CpG island shores. Nature Genetics 41 (2): 178–186.

Izzo A and Schneider R (2016) The role of linker histone H1 modifications in the regulation of gene expression and chromatin dynamics. Biochimica et Biophysica Acta 1859 (3): 486–495.

Jin P, Kang Q, Wang X, et al. (2015) Performance of a second‐generation methylated SEPT9 test in detecting colorectal neoplasm. Journal of Gastroenterology and Hepatology 30 (5): 830–833.

Kaminskas E, Farrell AT, Wang YC, Sridhara R and Pazdur R (2005) FDA drug approval summary: azacitidine (5‐azacytidine, Vidaza) for injectable suspension. Oncologist 10 (3): 176–182.

Kebede AF, Schneider R and Daujat S (2015) Novel types and sites of histone modifications emerge as players in the transcriptional regulation contest. FEBS Journal 282 (9): 1658–1674.

Kim JK, Samaranayake M and Pradhan S (2009) Epigenetic mechanisms in mammals. Cellular and Molecular Life Sciences 66 (4): 596–612.

Kleinjan DA, Seawright A, Childs AJ and van Heyningen V (2004) Conserved elements in Pax6 intron 7 involved in (auto)regulation and alternative transcription. Developmental Biology 265 (2): 462–477.

Lalonde ME, Avvakumov N, Glass KC, et al. (2013) Exchange of associated factors directs a switch in HBO1 acetyltransferase histone tail specificity. Genes and Development 27 (18): 2009–2024.

Li H, Ilin S, Wang W, et al. (2006) Molecular basis for site‐specific read‐out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442 (7098): 91–95.

Li J, Huang Q, Zeng F, et al. (2014) The prognostic value of global DNA hypomethylation in cancer: a meta‐analysis. PLoS One 9 (9): e106290.

Lou S, Lee HM, Qin H, et al. (2014) Whole‐genome bisulfite sequencing of multiple individuals reveals complementary roles of promoter and gene body methylation in transcriptional regulation. Genome Biology 15 (7): 408.

Lu C, Ward PS, Kapoor GS, et al. (2012) IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483 (7390): 474–478.

Medvedeva YA, Khamis AM, Kulakovskiy IV, et al. (2014) Effects of cytosine methylation on transcription factor binding sites. BMC Genomics 15: 119.

Naveja JJ and Medina‐Franco JL (2015) Activity landscape of DNA methyltransferase inhibitors bridges chemoinformatics with epigenetic drug discovery. Expert Opinion on Drug Discovery 10 (10): 1059–1070.

Ooi SK, Qiu C, Bernstein E, et al. (2007) DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448 (7154): 714–717.

Otani J, Nankumo T, Arita K, et al. (2009) Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX‐DNMT3‐DNMT3L domain. EMBO Reports 10 (11): 1235–1241.

Plass C, Pfister SM, Lindroth AM, et al. (2013) Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nature Reviews Genetics 14 (11): 765–780.

Sandoval J, Heyn H, Moran S, et al. (2011) Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 6 (6): 692–702.

Saxonov S, Berg P and Brutlag DL (2006) A genome‐wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proceedings of the National Academy of Sciences of the United States of America 103 (5): 1412–1417.

Takai D and Jones PA (2002) Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proceedings of the National Academy of Sciences of the United States of America 99 (6): 3740–3745.

Tamagawa H, Oshima T, Numata M, et al. (2013) Global histone modification of H3K27 correlates with the outcomes in patients with metachronous liver metastasis of colorectal cancer. European Journal of Surgical Oncology 39 (6): 655–661.

Thambirajah AA, Li A, Ishibashi T and Ausio J (2009) New developments in post‐translational modifications and functions of histone H2A variants. Biochemistry and Cell Biology 87 (1): 7–17.

The Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513 (7517): 202–209.

Timp W and Feinberg AP (2013) Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nature Reviews Cancer 13 (7): 497–510.

Varley KE, Gertz J, Bowling KM, et al. (2013) Dynamic DNA methylation across diverse human cell lines and tissues. Genome Research 23 (3): 555–567.

Vermeulen M, Mulder KW, Denissov S, et al. (2007) Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131 (1): 58–69.

Wallace TJ, Torre T, Grob M, et al. (2014) Current approaches, challenges and future directions for monitoring treatment response in prostate cancer. Journal of Cancer 5 (1): 3–24.

Ward PS, Patel J, Wise DR, et al. (2010) The common feature of leukemia‐associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha‐ketoglutarate to 2‐hydroxyglutarate. Cancer Cell 17 (3): 225–234.

Weinstein JN, Collisson EA, Mills GB, et al. (2013) The Cancer Genome Atlas Pan‐Cancer analysis project. Nature Genetics 45 (10): 1113–1120.

Witte T, Plass C and Gerhauser C (2014) Pan‐cancer patterns of DNA methylation. Genome Medicine 6 (8): 66.

Wysocka J, Swigut T, Xiao H, et al. (2006) A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442 (7098): 86–90.

Yoruker EE, Holdenrieder S and Gezer U (2016) Blood‐based biomarkers for diagnosis, prognosis and treatment of colorectal cancer. Clinica Chimica Acta 455: 26–32.

Zhao QT, Guo T, Wang HE, et al. (2015) Diagnostic value of SHOX2 DNA methylation in lung cancer: a meta‐analysis. Onco Targets and Therapy 8: 3433–3439.

Further Reading

Dimitrova E, Turberfield AH and Klose RJ (2015) Histone demethylases in chromatin biology and beyond. EMBO Reports 16 (12): 1620–1639.

Huang WY, Hsu SD, Huang HY, et al. (2015) MethHC: a database of DNA methylation and gene expression in human cancer. Nucleic Acids Research 43 (Database issue): D856–D861.

Jankowska AM, Millward CL and Caldwell CW (2015) The potential of DNA modifications as biomarkers and therapeutic targets in oncology. Expert Review of Molecular Diagnostics 15 (10): 1325–1337.

Khare SP, Habib F, Sharma R, et al. (2012) HIstome – a relational knowledgebase of human histone proteins and histone modifying enzymes. Nucleic Acids Research 40 (Database issue): D337–D342.

Kulis M, Queiros AC, Beekman R and Martin‐Subero JI (2013) Intragenic DNA methylation in transcriptional regulation, normal differentiation and cancer. Biochimica et Biophysica Acta 1829 (11): 1161–1174.

Lawrence M, Daujat S and Schneider R (2016) Lateral thinking: how histone modifications regulate gene expression. Trends in Genetics 32 (1): 42–56.

Raney BJ, Dreszer TR, Barber GP, et al. (2014) Track data hubs enable visualization of user‐defined genome‐wide annotations on the UCSC Genome Browser. Bioinformatics 30 (7): 1003–1005.

Riedel SS, Neff T and Bernt KM (2015) Histone profiles in cancer. Pharmacology and Therapeutics 154: 87–109.

Rose NR and Klose RJ (2014) Understanding the relationship between DNA methylation and histone lysine methylation. Biochimica et Biophysica Acta 1839 (12): 1362–1372.

Shinjo K and Kondo Y (2015) Targeting cancer epigenetics: linking basic biology to clinical medicine. Advanced Drug Delivery Reviews 95: 56–64.

Web Links

A database of clinical trials, https://clinicaltrials.gov/

A database of DNA methylation and gene expression in human cancer, http://methhc.mbc.nctu.edu.tw/

HIstome: The Histone Infobase, http://www.actrec.gov.in/histome/index.php

The Cancer Genome Atlas (TCGA) Research Network, http://cancergenome.nih.gov/

The Encyclopedia of DNA Elements (ENCODE) Consortium project, http://www.ensembl.org/info/website/tutorials/encode.html and https://www.encodeproject.org/

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Hudler, Petra(Jul 2016) Aberrant DNA Methylation and Histone Modifications in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026336]