Skip to main content
SpringerLink
Log in

Aberrant DNA methylation in human cancers

  • Published:
Journal of Huazhong University of Science and Technology [Medical Sciences] Aims and scope Submit manuscript

Summary

DNA methylation, one of the best-characterized epigenetic modifications, plays essential roles in diseases, including human cancers. In recent years, our understanding on DNA methylation with human cancers has made significant progress, which was facilitated by stunning development in the analysis of the human methylome of multiple cancer types. In this review, recent developments in the characterization of aberrant DNA methylation involved in human cancers development were discussed with special emphasis on the mechanisms of aberrant DNA methylation in human cancers. We also summarize the recent treatment strategy for human cancers with de-methylation drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Esteller M. Cancer epigenetics for the 21st century: What’s next? Genes Cancer, 2011,2(6):604–606

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  2. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis, 2010,31(1):27–36

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  3. Esteller M. Aberrant DNA methylation as a cancer-inducing mechanism. Annu Rev Pharmacol Toxicol, 2005,45:629–656

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Medvedeva YA, Fridman MV, Oparina NJ, et al. Intergenic, gene terminal, and intragenic CpG islands in the human genome. BMC Genomics, 2010,11:48

    Article  PubMed Central  PubMed  Google Scholar 

  6. Lan J, Hua S, He X, et al. DNA methyltransferases and methyl-binding proteins of mammals. Acta Biochim Biophys Sin (Shanghai), 2010,42(4):243–252

    Article  CAS  Google Scholar 

  7. Dhe-Paganon S, Syeda F, Park L. DNA methyltransferase 1: regulatory mechanisms and implications in health and disease. Int J Biochem Mol Biol, 2011,2(1):58–66

    PubMed Central  PubMed  CAS  Google Scholar 

  8. Okano M, Bell DW, Haber DA, et al. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell, 1999,99(3):247–257

    Article  PubMed  CAS  Google Scholar 

  9. Thiagarajan D, Dev RR, Khosla S. The DNA methyltranferase Dnmt2 participates in RNA processing during cellular stress. Epigenetics, 2011,6(1):103–113

    Article  PubMed  CAS  Google Scholar 

  10. Suetake I, Shinozaki F, Miyagawa J, et al. DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction. J Biol Chem, 2004,279(26):27 816–27 823

    Article  CAS  Google Scholar 

  11. Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene, 2002,21(35):5427–5440

    Article  PubMed  CAS  Google Scholar 

  12. Fournier A, Sasai N, Nakao M, et al. The role of methyl-binding proteins in chromatin organization and epigenome maintenance. Brief Funct Genomics, 2012,11(3):251–264

    Article  PubMed  CAS  Google Scholar 

  13. Defossez PA, Stancheva I. Biological functions of methyl-CpG-binding proteins. Prog Mol Biol Transl Sci, 2011,101:377–398

    Article  PubMed  CAS  Google Scholar 

  14. Ai T, Cui H, Chen L. Multi-targeted histone deacetylase inhibitors in cancer therapy. Curr Med Chem, 2012,19(4):475–487

    Article  PubMed  CAS  Google Scholar 

  15. Das PM, Singal R. DNA methylation and cancer. J Clin Oncol, 2004,22(22):4632–4642

    Article  PubMed  CAS  Google Scholar 

  16. Kulis M, Esteller M. DNA methylation and cancer. Adv Genet, 2010,70:27–56

    Article  PubMed  Google Scholar 

  17. Torano EG, Petrus S, Fernandez AF, et al. Global DNA hypomethylation in cancer: review of validated methods and clinical significance. Clin Chem Lab Med, 2012,50(10):1733–1742

    Article  PubMed  CAS  Google Scholar 

  18. Daura-Oller E, Cabre M, Montero MA, et al. Specific gene hypomethylation and cancer: new insights into coding region feature trends. Bioinformation, 2009,3(8):340–343

    Article  PubMed Central  PubMed  Google Scholar 

  19. Ehrlich M. DNA hypomethylation in cancer cells. Epigenomics, 2009,1(2):239–259

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Herceg Z, Ushijima T. Introduction: epigenetics and cancer. Adv Genet, 2010,70:1–23

    Article  PubMed  Google Scholar 

  21. Denis H, Ndlovu MN, Fuks F. Regulation of mammalian DNA methyltransferases: a route to new mechanisms. EMBO Rep, 2011,12(7):647–656

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by micro- RNAs: are the answers in sight? Nat Rev Genet, 2008,9(2):102–114

    Article  PubMed  CAS  Google Scholar 

  23. Fabbri M, Garzon R, Cimmino A, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA, 2007,104(40):15 805–15 810

    Article  CAS  Google Scholar 

  24. Garzon R, Liu S, Fabbri M, et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood, 2009,113(25):6411–6418

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Duursma AM, Kedde M, Schrier M, et al. miR-148 targets human DNMT3b protein coding region. RNA, 2008,14(5):872–877

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  26. Braconi C, Huang NY, Patel T. MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes. Hepatology, 2010,51(3):881–890

    PubMed Central  PubMed  CAS  Google Scholar 

  27. Huang J, Wang Y, Guo Y, et al. Down-regulated microRNA-152 induces aberrant DNA methylation in hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology, 2010,52(1):60–70

    Article  PubMed  CAS  Google Scholar 

  28. Pan W, Zhu S, Yuan M, et al. MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1. J Immunol, 2010,184(12):6773–6781

    Article  PubMed  CAS  Google Scholar 

  29. Zhao S, Wang Y, Liang Y, et al. MicroRNA-126 regulates DNA methylation in CD4+ T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1. Arthritis Rheum, 2011,63(5):1376–1386

    Article  PubMed  CAS  Google Scholar 

  30. Chen BF, Gu S, Suen YK, et al. microRNA-199a-3p, DNMT3A, and aberrant DNA methylation in testicular cancer. Epigenetics, 2013,9(1):1–8

    Google Scholar 

  31. Krueger KE, Srivastava S. Posttranslational protein modifications: current implications for cancer detection, prevention, and therapeutics. Mol Cell Proteomics, 2006,5(10):1799–1810

    Article  PubMed  CAS  Google Scholar 

  32. Hann SR. Role of post-translational modifications in regulating c-Myc proteolysis, transcriptional activity and biological function. Semin Cancer Biol, 2006,16(4):288–302

    Article  PubMed  CAS  Google Scholar 

  33. Li H, Rauch T, Chen ZX, et al. The histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells. J Biol Chem, 2006,281(28):19 489–19 500

    Article  CAS  Google Scholar 

  34. Esteve PO, Chin HG, Benner J, et al. Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells. Proc Natl Acad Sci USA, 2009,106(13):5076–5081

    Article  PubMed Central  PubMed  Google Scholar 

  35. Lavoie G, Esteve PO, Laulan NB, et al. PKC isoforms interact with and phosphorylate DNMT1. Bmc Biology, 2011,9:31

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  36. Ling Y, Sankpal UT, Robertson AK, et al. Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription. Nucleic Acids Res, 2004,32(2):598–610

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  37. Kang ES, Park CW, Chung JH. Dnmt3b, de novo DNA methyltransferase, interacts with SUMO-1 and Ubc9 through its N-terminal region and is subject to modification by SUMO-1. Biochem Biophys Res Commun, 2001,289(4):862–868

    Article  PubMed  CAS  Google Scholar 

  38. Lee B, Muller MT. SUMOylation enhances DNA methyltransferase 1 activity. Biochem J, 2009,421(3):449–461

    Article  PubMed  CAS  Google Scholar 

  39. Wang J, Hevi S, Kurash JK, et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet, 2009,41(1):125–129

    Article  PubMed  CAS  Google Scholar 

  40. Glickman JF, Pavlovich JG, Reich NO. Peptide mapping of the murine DNA methyltransferase reveals a major phosphorylation site and the start of translation. J Biol Chem, 1997,272(28):17 851–17 857

    Article  CAS  Google Scholar 

  41. Goyal R, Rathert P, Laser H, et al. Phosphorylation of serine-515 activates the mammalian maintenance methyltransferase Dnmt1. Epigenetics, 2007,2(3):155–160

    Article  PubMed  Google Scholar 

  42. Kameshita I, Sekiguchi M, Hamasaki D, et al. Cyclin-dependent kinase-like 5 binds and phosphorylates DNA methyltransferase 1. Biochem Biophys Res Commun, 2008,377(4):1162–1167

    Article  PubMed  CAS  Google Scholar 

  43. Sugiyama Y, Hatano N, Sueyoshi N, et al. The DNA-binding activity of mouse DNA methyltransferase 1 is regulated by phosphorylation with casein kinase 1delta/epsilon. Biochem J, 2010,427(3):489–497

    Article  PubMed  CAS  Google Scholar 

  44. Hervouet E, Lalier L, Debien E, et al. Disruption of Dnmt1/PCNA/UHRF1 interactions promotes tumorigenesis from human and mice glial cells. PLoS One, 2010, 5(6):e11333

    Article  PubMed Central  PubMed  Google Scholar 

  45. Niessen HE, Demmers JA, Voncken JW. Talking to chromatin: post-translational modulation of polycomb group function. Epigenetics Chromatin, 2009,2(1):10

    Article  PubMed Central  PubMed  Google Scholar 

  46. Rountree MR, Bachman KE, Herman JG, et al. DNA methylation, chromatin inheritance, and cancer. Oncogene, 2001,20(24):3156–3165

    Article  PubMed  CAS  Google Scholar 

  47. Graff JR, Herman JG, Lapidus RG, et al. E-Cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res, 1995,55(22):5195–5199

    PubMed  CAS  Google Scholar 

  48. Du W, Searle JS. The rb pathway and cancer therapeutics. Curr Drug Targets, 2009,10(7):581–589

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  49. Cheng NC, Beitsma M, Chan A, et al. Lack of class I HLA expression in neuroblastoma is associated with high N-myc expression and hypomethylation due to loss of the MEMO-1 locus. Oncogene, 1996,13(8):1737–1744

    PubMed  CAS  Google Scholar 

  50. Cheng NC, Chan AJK, Beitsma MM, et al. A human modifier of methylation for class I HLA genes (MEMO-1) maps to chromosomal bands 1p35–36.1. Hum Mol Genet, 1996,5(3):309–317

    Article  PubMed  CAS  Google Scholar 

  51. Wu JJ, Issa JP, Herman J, et al. Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of Nih-3t3 cells. Proc Natl Acad Sci USA, 1993,90(19):8891–8895

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  52. Vertino PM, Yen RWC, Gao J, et al. De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5)-methyltransferase. Mol Cell Biol, 1996,16(8):4555–4565

    PubMed Central  PubMed  CAS  Google Scholar 

  53. Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet, 2000,25(3):269–277

    Article  PubMed  CAS  Google Scholar 

  54. Kennedy BK, Barbie DA, Classon M, et al. Nuclear organization of DNA replication in primary mammalian cells. Genes Dev, 2000,14(22):2855–2868

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  55. Harbour JW, Dean DC. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev, 2000,14(19):2393–2409

    Article  PubMed  CAS  Google Scholar 

  56. Harbour JW, Dean DC. Chromatin remodeling and Rb activity. Curr Opin Cell Biol, 2000,12(6):685–689

    Article  PubMed  CAS  Google Scholar 

  57. Sahin M, Sahin E, Gumuslu S, et al. DNA methylation or histone modification status in metastasis and angiogenesis-related genes: a new hypothesis on usage of DNMT inhibitors and S-adenosylmethionine for genome stability. Cancer Metastasis Rev, 2010,29(4):655–676

    Article  PubMed  CAS  Google Scholar 

  58. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell, 1980,20(1):85–93

    Article  PubMed  CAS  Google Scholar 

  59. Goffin J, Eisenhauer E. DNA methyltransferase inhibitors-state of the art. Ann Oncol, 2002,13(11):1699–1716

    Article  PubMed  CAS  Google Scholar 

  60. El-Osta A. Review on epigenetics in cancer gene therapy: series I. Cancer Gene Therapy, 2005,12(8):663–664

    Article  CAS  Google Scholar 

  61. Cheng JC, Yoo CB, Weisenberger DJ, et al. Preferential response of cancer cells to zebularine. Cancer Cell, 2004,6(2):151–158

    Article  PubMed  CAS  Google Scholar 

  62. Segura-Pacheco B, Trejo-Becerril C, Perez-Cardenas E, et al. Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy. Clin Cancer Res, 2003,9(5):1596–1603

    PubMed  CAS  Google Scholar 

  63. Yan L, Nass SJ, Smith D, et al. Specific inhibition of DNMT1 by antisense oligonucleotides induces re-expression of estrogen receptor alpha (ER) in ER-negative human breast cancer cell lines. Cancer Biol Therapy, 2003,2(5):552–556

    Article  CAS  Google Scholar 

  64. Tan J, Yang XJ, Zhuang L, et al. Pharmacologic disruption of polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev, 2007,21(9):1050–1063

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  65. Gal-Yam EN, Saito Y, Egger G, et al. Cancer epigenetics: Modifications, screening, and therapy. Ann Rev Med, 2008,59:267–280

    Article  PubMed  CAS  Google Scholar 

  66. Huang Y, Greene E, Stewart TM, et al. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc Natl Acad Sci USA, 2007,104(19):8023–8028

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  67. Loh YH, Zhang W, Chen X, et al. Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev, 2007,21(20):2545–2557

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  68. Decarlo D, Hadden MK. Oncoepigenomics: Making histone lysine methylation count. Eur J Med Chem, 2012,56:179–194

    Article  PubMed  CAS  Google Scholar 

  69. Akhavan-Niaki H, Samadani AA. DNA methylation and cancer development: Molecular mechanism. Cell Biochem Biophys, 2013,67(2):501–513

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Editorial Department of Journal of Clinical Surgery, Hubei Medical Association, Wuhan, 430071, China

    Wen Li  (黎 文)

  2. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China

    Bi-feng Chen  (陈碧峰)

Authors
  1. Wen Li  (黎 文)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bi-feng Chen  (陈碧峰)
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bi-feng Chen  (陈碧峰).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, W., Chen, Bf. Aberrant DNA methylation in human cancers. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 33, 798–804 (2013). https://doi.org/10.1007/s11596-013-1201-0

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-013-1201-0

Key words

Search

Navigation