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The rise and fall of genomic methylation in cancer

Leukemia volume 18, pages 233–237 (2004)Cite this article

Abstract

Changes in genomic methylation and its significance in carcinogenesis is in the spotlight once again, though the focus is not on the usual suspects, DNA hypermethylation and tumour suppressor gene (TSG) silencing. Several recent reports provide compelling evidence of the relevance of genomic hypomethylation in cancer. These findings provide the best evidence so far that links the loss of DNA methylation and chromosomal instability with cancer development. This review article discusses these recent findings and reflects on the antithetical association between DNA methylation and carcinogenesis and the re-examination of studies performed almost two decades ago.

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References

  1. Jones PA, Baylin SB . The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3: 415–428.

    Article  CAS  Google Scholar 

  2. Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW et al. Induction of tumors in mice by genomic hypomethylation. Science 2003; 300: 489–492.

    Article  CAS  PubMed  Google Scholar 

  3. Eden A, Gaudet F, Waghmare A, Jaenisch R . Chromosomal instability and tumors promoted by DNA hypomethylation. Science 2003; 300: 455.

    Article  CAS  PubMed  Google Scholar 

  4. Feinberg AP, Vogelstein B . Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 1983; 301: 89–92.

    Article  CAS  PubMed  Google Scholar 

  5. Jones PA, Laird PW . Cancer epigenetics comes of age. Nat Genet 1999; 21: 163–167.

    Article  CAS  PubMed  Google Scholar 

  6. Baylin S, Bestor TH . Altered methylation patterns in cancer cell genomes: cause or consequence? Cancer Cell 2002; 1: 299–305.

    Article  CAS  Google Scholar 

  7. Baylin SB, Herman JG . DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 2000; 16: 168–174.

    Article  CAS  Google Scholar 

  8. Melki JR, Clark SJ . DNA methylation changes in leukaemia. Semin Cancer Biol 2002; 12: 347–357.

    Article  CAS  PubMed  Google Scholar 

  9. Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP . Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet 2000; 25: 315–319.

    Article  CAS  Google Scholar 

  10. Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van Engeland M, Weijenberg MP et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 2002; 31: 141–149.

    Article  CAS  Google Scholar 

  11. Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 2002; 416: 552–556.

    Article  CAS  PubMed  Google Scholar 

  12. Rhee I, Jair KW, Yen RW, Lengauer C, Herman JG, Kinzler KW et al. CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 2000; 404: 1003–1007.

    Article  CAS  PubMed  Google Scholar 

  13. Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R, Kuo KC, Gehrke CW et al. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res 1983; 11: 6883–6894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Carr BI, Reilly JG, Smith SS, Winberg C, Riggs A . The tumorigenicity of 5-azacytidine in the male Fischer rat. Carcinogenesis 1984; 5: 1583–1590.

    Article  CAS  PubMed  Google Scholar 

  15. Cheng JC, Matsen CB, Gonzales FA, Ye W, Greer S, Marquez VE et al. Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J Natl Cancer Inst 2003; 95: 399–409.

    Article  CAS  PubMed  Google Scholar 

  16. Xu GL, Bestor TH, Bourc'his D, Hsieh CL, Tommerup N, Bugge M et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 1999; 402: 187–191.

    Article  CAS  PubMed  Google Scholar 

  17. Carpenter NJ, Filipovich A, Blaese RM, Carey TL, Berkel AI . Variable immunodeficiency with abnormal condensation of the heterochromatin of chromosomes 1, 9, and 16. J Pediatr 1988; 112: 757–760.

    Article  CAS  PubMed  Google Scholar 

  18. Jeanpierre M, Turleau C, Aurias A, Prieur M, Ledeist F, Fischer A et al. An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome. Hum Mol Genet 1993; 2: 731–735.

    Article  CAS  PubMed  Google Scholar 

  19. Miniou P, Jeanpierre M, Blanquet V, Sibella V, Bonneau D, Herbelin C et al. Abnormal methylation pattern in constitutive and facultative (X inactive chromosome) heterochromatin of ICF patients. Hum Mol Genet 1994; 3: 2093–2102.

    Article  CAS  PubMed  Google Scholar 

  20. Hansen RS, Stoger R, Wijmenga C, Stanek AM, Canfield TK, Luo P et al. Escape from gene silencing in ICF syndrome: evidence for advanced replication time as a major determinant. Hum Mol Genet 2000; 9: 2575–2587.

    Article  CAS  PubMed  Google Scholar 

  21. Okano M, Bell DW, Haber DA, Li E . DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999; 99: 247–257.

    Article  CAS  Google Scholar 

  22. Li E, Bestor TH, Jaenisch R . Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 1992; 69: 915–926.

    Article  CAS  Google Scholar 

  23. Lei H, Oh SP, Okano M, Juttermann R, Goss KA, Jaenisch R et al. De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development 1996; 122: 3195–3205.

    CAS  PubMed  Google Scholar 

  24. Cichowski K, Shih TS, Schmitt E, Santiago S, Reilly K, McLaughlin ME et al. Mouse models of tumor development in neurofibromatosis type 1. Science 1999; 286: 2172–2176.

    Article  CAS  PubMed  Google Scholar 

  25. Almeida A, Kokalj-Vokac N, Lefrancois D, Viegas-Pequignot E, Jeanpierre M, Dutrillaux B et al. Hypomethylation of classical satellite DNA and chromosome instability in lymphoblastoid cell lines. Hum Genet 1993; 91: 538–546.

    Article  CAS  PubMed  Google Scholar 

  26. Ahuja N, Mohan AL, Li Q, Stolker JM, Herman JG, Hamilton SR et al. Association between CpG island methylation and microsatellite instability in colorectal cancer. Cancer Res 1997; 57: 3370–3374.

    CAS  Google Scholar 

  27. Strand M, Prolla TA, Liskay RM, Petes TD . Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature 1993; 365: 274–276.

    Article  CAS  PubMed  Google Scholar 

  28. Prolla TA, Baker SM, Harris AC, Tsao JL, Yao X, Bronner CE et al. Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repair. Nat Genet 1998; 18: 276–279.

    Article  CAS  PubMed  Google Scholar 

  29. Trinh BN, Long TI, Nickel AE, Shibata D, Laird PW . DNA methyltransferase deficiency modifies cancer susceptibility in mice lacking DNA mismatch repair. Mol Cell Biol 2002; 22: 2906–2917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R . DNA hypomethylation leads to elevated mutation rates. Nature 1998; 395: 89–93.

    Article  CAS  Google Scholar 

  31. El-Osta A, Wolffe AP . DNA methylation and histone deacetylation in the control of gene expression: basic biochemistry to human development and disease. Gene Expr 2000; 9: 63–75.

    Article  CAS  PubMed  Google Scholar 

  32. Okano M, Bell DW, Haber DA, Li E . DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999; 99: 247–257.

    Article  CAS  Google Scholar 

  33. Jeanpierre M, Turleau C, Aurias A, Prieur M, Ledeist F, Fischer A et al. An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome. Hum Mol Genet 1993; 2: 731–735.

    Article  CAS  PubMed  Google Scholar 

  34. Gowher H, Jeltsch A . Molecular enzymology of the catalytic domains of the Dnmt3a and Dnmt3b DNA methyltransferases. J Biol Chem 2002; 277: 20409–20414.

    Article  CAS  PubMed  Google Scholar 

  35. Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM et al. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci USA 1999; 96: 14412–14417.

    Article  CAS  Google Scholar 

  36. Wang X, Babu JR, Harden JM, Jablonski SA, Gazi MH, Lingle WL et al. The mitotic checkpoint protein hBUB3 and the mRNA export factor hRAE1 interact with GLE2p-binding sequence (GLEBS)-containing proteins. J Biol Chem 2001; 276: 26559–26567.

    Article  CAS  PubMed  Google Scholar 

  37. Babu JR, Jeganathan KB, Baker DJ, Wu X, Kang-Decker N, van Deursen JM . Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J Cell Biol 2003; 160: 341–353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD et al. Mutations of mitotic checkpoint genes in human cancers. Nature 1998; 392: 300–303.

    Article  CAS  Google Scholar 

  39. Wei Y, Yu L, Bowen J, Gorovsky MA, Allis CD . Phosphorylation of histone H3 is required for proper chromosome condensation and segregation. Cell 1999; 97: 99–109.

    Article  CAS  PubMed  Google Scholar 

  40. Peters AH, O'Carroll D, Scherthan H, Mechtler K, Sauer S, Schofer C et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 2001; 107: 323–337.

    Article  CAS  PubMed  Google Scholar 

  41. Strahl BD, Allis CD . The language of covalent histone modifications. Nature 2000; 403: 41–45.

    Article  CAS  Google Scholar 

  42. Santos-Rosa H, Schneider R, Bannister AJ, Sherriff J, Bernstein BE, Emre NC et al. Active genes are tri-methylated at K4 of histone H3. Nature 2002; 419: 407–411.

    Article  CAS  PubMed  Google Scholar 

  43. Bernstein BE, Humphrey EL, Erlich RL, Schneider R, Bouman P, Liu JS et al. Methylation of histone H3 Lys 4 in coding regions of active genes. Proc Natl Acad Sci USA 2002; 99: 8695–8700.

    Article  CAS  PubMed  Google Scholar 

  44. Schotta G, Ebert A, Krauss V, Fischer A, Hoffmann J, Rea S et al. Central role of Drosophila SU(VAR)3-9 in histone H3-K9 methylation and heterochromatic gene silencing. EMBO J 2002; 21: 1121–1131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Johnson L, Cao X, Jacobsen S . Interplay between two epigenetic marks. DNA methylation and histone H3 lysine 9 methylation. Curr Biol 2002; 12: 1360–1367.

    Article  CAS  PubMed  Google Scholar 

  46. Heard E, Rougeulle C, Arnaud D, Avner P, Allis CD, Spector DL . Methylation of histone H3 at Lys-9 is an early mark on the X chromosome during X inactivation. Cell 2001; 107: 727–738.

    Article  CAS  PubMed  Google Scholar 

  47. Nakayama J, Rice JC, Strahl BD, Allis CD, Grewal SI . Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 2001; 292: 110–113.

    Article  CAS  PubMed  Google Scholar 

  48. Rea S, Eisenhaber F, O'Carroll D, Strahl BD, Sun ZW, Schmid M et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 2000; 406: 593–599.

    Article  CAS  PubMed  Google Scholar 

  49. Briggs SD, Bryk M, Strahl BD, Cheung WL, Davie JK, Dent SY et al. Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae. Genes Dev 2001; 15: 3286–3295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lachner M, Jenuwein T . The many faces of histone lysine methylation. Curr Opin Cell Biol 2002; 14: 286–298.

    Article  CAS  PubMed  Google Scholar 

  51. Tamaru H, Selker EU . A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 2001; 414: 277–283.

    Article  CAS  PubMed  Google Scholar 

  52. Jackson JP, Lindroth AM, Cao X, Jacobsen SE . Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 2002; 416: 556–560.

    Article  CAS  PubMed  Google Scholar 

  53. Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S et al. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr Biol 2003; 13: 1192–1200.

    Article  CAS  PubMed  Google Scholar 

  54. Eads CA, Danenberg KD, Kawakami K, Saltz LB, Danenberg PV, Laird PW . CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res 1999; 59: 2302–2306.

    CAS  PubMed  Google Scholar 

  55. Dennis K, Fan T, Geiman T, Yan Q, Muegge K . Lsh, a member of the SNF2 family, is required for genome-wide methylation. Genes Dev 2001; 15: 2940–2944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bachman KE, Park BH, Rhee I, Rajagopalan H, Herman JG, Baylin SB et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 2003; 3: 89–95.

    Article  CAS  Google Scholar 

  57. El-Osta A, Kantharidis P, Zalcberg JR, Wolffe AP . Precipitous release of methyl-CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation. Mol Cell Biol 2002; 22: 1844–1857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Magdinier F, Wolffe AP . Selective association of the methyl-CpG binding protein MBD2 with the silent p14/p16 locus in human neoplasia. Proc Natl Acad Sci USA 2001; 98: 4990–4995.

    Article  CAS  PubMed  Google Scholar 

  59. Tariq M, Saze H, Probst AV, Lichota J, Habu Y, Paszkowski J . Erasure of CpG methylation in Arabidopsis alters patterns of histone H3 methylation in heterochromatin. Proc Natl Acad Sci USA 2003; 100: 8823–8827.

    Article  CAS  PubMed  Google Scholar 

  60. Weissmann F, Muyrers-Chen I, Musch T, Stach D, Wiessler M, Paro R et al. DNA hypermethylation in Drosophila melanogaster causes irregular chromosome condensation and dysregulation of epigenetic histone modifications. Mol Cell Biol 2003; 23: 2577–2586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tamaru H, Zhang X, McMillen D, Singh PB, Nakayama J, Grewal SI et al. Trimethylated lysine 9 of histone H3 is a mark for DNA methylation in Neurospora crassa. Nat Genet 2003; 34: 75–79.

    Article  CAS  PubMed  Google Scholar 

  62. Kouzminova E, Selker EU . dim-2 encodes a DNA methyltransferase responsible for all known cytosine methylation in Neurospora. EMBO J 2001; 20: 4309–4323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. The Alfred Medical Research and Education Precinct (AMREP), Epigenetics in Human Health and Disease Laboratory, Baker Medical Research Institute, Prahran, Victoria, Australia

    Assam El-Osta

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El-Osta, A. The rise and fall of genomic methylation in cancer. Leukemia 18, 233–237 (2004). https://doi.org/10.1038/sj.leu.2403218

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