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Reactivating the expression of methylation silenced genes in human cancer

Abstract

DNA methylation alterations are now widely recognized as a contributing factor in human tumorigenesis. A significant number of tumor suppressor genes are transcriptionally silenced by promoter hypermethylation, and recent research implicates alterations in chromatin structure as the mechanistic basis for this repression. The enzymes responsible for catalyzing DNA-cytosine methylation, as well as the proteins involved in interpreting the DNA methylation signal, have now been elucidated. Technological advances, including gene expression microarrays and genome scanning techniques, have allowed the comprehensive measurement of DNA methylation changes in human cancers. An important distinction between DNA methylation (epigenetic) and mutation or deletion (genetic) tumor suppressor gene inactivation is that epigenetic inactivation can be abrogated by small molecules, including DNA methyltransferase and histone deacetylase inhibitors. Further, strategies have been developed that combine treatments with drugs that reactivate silenced gene expression with secondary agents that target the re-expressed genes and/or reconstituted signal transduction pathways. In this review, we will discuss in detail the mechanisms of gene silencing by DNA methylation, the techniques used to decipher the complement of methylation-inactivated genes in human cancers, and current and future strategies for reactivating the expression of methylation-silenced genes.

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References

  • Abril E, Real LM, Serrano A, Jimenez P, Garcia A, Canton J, Trigo I, Garrido F, Ruiz-Cabello F . 1998 Cancer Immunol. Immunother. 47: 113–120

  • Albanesi T, Polani S, Cozzi R, Perticone P . 1999 Mutat. Res. 429: 239–248

  • Altucci L, Gronemeyer H . 2001 Nat. Rev. Cancer 1: 181–193

  • Bachman KE, Rountree MR, Baylin SB . 2001 J. Biol. Chem. 276: 32282–32287

  • Baylin SB, Herman JG . 2000 Trends Genet. 16: 168–174

  • Bender CM, Gonzalgo ML, Gonzales FA, Nguyen CT, Robertson KD, Jones PA . 1999 Mol. Cell. Biol. 19: 6690–6698

  • Bender CM, Zingg JM, Jones PA . 1998 Pharm. Res. 15: 175–187

  • Bigey P, Knox JD, Croteau S, Bhattacharya SK, Theberge J, Szyf M . 1999 J. Biol. Chem. 274: 4594–4606

  • Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB . 1999 Nat. Genet. 21: 103–107

  • Cervoni N, Szyf M . 2001 J. Biol. Chem. 276: 40778–40787

  • Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R . 1998 Nature 395: 89–93

  • Clark SJ, Harrison J, Molloy PL . 1997 Gene 195: 67–71

  • Costello JF, Fruhwald MC, Smiraglia D, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomaki P, Lang JC, Schuller DE, Yu L, Bloomfield CD, Caligiuri MA, Yates A, Nishikawa R, Su Huang H, Petrelli NJ, Zhang X, O'Dorisio MS, Held WA, Cavenee WK, Plass C . 2000 Nat. Genet. 24: 132–138

  • Cote S, Sinnett D, Momparler RL . 1998 Anticancer Drugs 9: 743–750

  • De Smet C, De Backer O, Faraoni I, Lurquin C, Brasseur F, Boon T . 1996 Proc. Natl. Acad. Sci. USA 93: 7149–7153

  • Esteller M, Corn PG, Baylin SB, Herman JG . 2001 Cancer Res. 61: 3225–3229

  • Fang JY, Zhu SS, Xiao SD, Jiang SJ, Shi Y, Chen XY, Zhou XM, Qian LF . 1996 J. Gastroenterol. Hepatol. 11: 1079–1082

  • Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M . 1988 Cancer Res. 48: 1159–1161

  • Ferguson AT, Vertino PM, Spitzner JR, Baylin SB, Muller MT, Davidson NE . 1997 J. Biol. Chem. 272: 32260–32266

  • Fournel M, Sapieha P, Beaulieu N, Besterman JM, MacLeod AR . 1999 J. Biol. Chem. 274: 24250–24256

  • Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T . 2000 Nat Genet. 24: 88–91

  • Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T . 2001 EMBO J. 20: 2536–2544

  • Gaston K, Fried M . 1995 Nucl. Acids Res. 23: 901–909

  • Gillespie AM, Coleman RE . 1999 Cancer Treat. Rev. 25: 219–227

  • Hendrich B, Bird A . 1998 Mol. Cell. Biol. 18: 6538–6547

  • Jackson-Grusby L, Beard C, Possemato R, Tudor M, Fambrough D, Csankovszki G, Dausman J, Lee P, Wilson C, Lander E, Jaenisch R . 2001 Nat. Genet. 27: 31–39

  • Jackson-Grusby L, Laird PW, Magge SN, Moeller BJ, Jaenisch R . 1997 Proc. Natl. Acad. Sci. USA 94: 4681–4685

  • Jones DA, Karpf AR, Lasek A . 2001 Clin. Cancer Res. 7: 3827S–3827S

  • Jones PA, Laird PW . 1999 Nat. Genet. 21: 163–167

  • Jones PA, Taylor SM . 1980 Cell 20: 85–93

  • Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP . 1998 Nat. Genet. 19: 187–191

  • Juttermann R, Li E, Jaenisch R . 1994 Proc. Natl. Acad. Sci. USA 91: 11797–11801

  • Karpf AR, Moore BC, Ririe TO, Jones DA . 2001 Mol. Pharmacol. 59: 751–757

  • Karpf AR, Peterson PW, Rawlins JT, Dalley BK, Yang Q, Albertsen H, Jones DA . 1999 Proc. Natl. Acad. Sci. USA 96: 14007–14012

  • Kawai J, Hirotsune S, Hirose K, Fushiki S, Watanabe S, Hayashizaki Y . 1993 Nucl. Acids Res. 21: 5604–5608

  • Laird PW, Jackson-Grusby L, Fazeli A, Dickinson SL, Jung WE, Li E, Weinberg RA, Jaenisch R . 1995 Cell 81: 197–205

  • Lengauer C, Kinzler KW, Vogelstein B . 1997 Proc. Natl. Acad. Sci. USA 94: 2545–2550

  • Leshin M . 1985 Proc. Natl. Acad. Sci. USA 82: 3005–3009

  • Liang G, Gonzales FA, Jones PA, Orntoft TF, Thykjaer T . 2002 Cancer Res. 62: 961–966

  • Liu PQ, Rebar EJ, Zhang L, Liu Q, Jamieson AC, Liang Y, Qi H, Li PX, Chen B, Mendel MC, Zhong X, Lee YL, Eisenberg SP, Spratt SK, Case CC, Wolffe AP . 2001 J. Biol. Chem. 276: 11323–11334

  • Lubbert M . 2000 Curr. Top. Microbiol. Immunol. 249: 135–164

  • Magdinier F, Wolffe AP . 2001 Proc. Natl. Acad. Sci. USA 98: 4990–4995

  • Nan X, Campoy FJ, Bird A . 1997 Cell 88: 471–481

  • Neidhart M, Rethage J, Kuchen S, Kunzler P, Crowl RM, Billingham ME, Gay RE, Gay S . 2000 Arthritis Rheum. 43: 2634–2647

  • Ng HH, Jeppesen P, Bird A . 2000 Mol. Cell. Biol. 20: 1394–1406

  • Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Tempst P, Reinberg D, Bird A . 1999 Nat. Genet. 23: 58–61

  • Peller S, Yona R, Kopilova Y, Prokocimer M, Goldfinger N, Uysal A, Karabulut HG, Tukun A, Bokesoy I, Tuncman G, Rotter V . 1998 Genes Chrom. Cancer 21: 2–7

  • Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D . 2000 Nature 406: 747–752

  • Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R . 2000 Cancer Res. 60: 6039–6044

  • Robertson KD . 2001 Oncogene 20: 3139–3155

  • Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP . 2000 Nat. Genet. 25: 338–342

  • Rountree MR, Bachman KE, Baylin SB . 2000 Nat. Genet. 25: 269–277

  • Rountree MR, Bachman KE, Herman JG, Baylin SB . 2001 Oncogene 20: 3156–3165

  • Sacchi S, Kantarjian HM, O'Brien S, Cortes J, Rios MB, Giles FJ, Beran M, Koller CA, Keating MJ, Talpaz M . 1999 Cancer 86: 2632–2641

  • Schena M, Shalon D, Davis RW, Brown PO . 1995 Science 270: 467–470

  • Selker EU . 1998 Proc. Natl. Acad. Sci. USA 95: 9430–9435

  • Strathdee G, MacKean MJ, Illand M, Brown R . 1999 Oncogene 18: 2335–2341

  • Sun WH, Pabon C, Alsayed Y, Huang PP, Jandeska S, Uddin S, Platanias LC, Rosen ST . 1998 Blood 91: 570–576

  • Tamaru H, Selker EU . 2001 Nature 414: 277–283

  • Thibault A, Figg WD, Bergan RC, Lush RM, Myers CE, Tompkins A, Reed E, Samid D . 1998 Tumori 84: 87–89

  • Umezawa A, Yamamoto H, Rhodes K, Klemsz MJ, Maki RA, Oshima RG . 1997 Mol. Cell. Biol. 17: 4885–4894

  • Wade PA . 2001 Oncogene 20: 3166–3173

  • Wang R, Yu Z, Gu J, Li D, Wang M, Cao Y . 1998 Chin. Med. J. (Engl.) 111: 339–342

  • Weber J, Salgaller M, Samid D, Johnson B, Herlyn M, Lassam N, Treisman J, Rosenberg SA . 1994 Cancer Res. 54: 1766–1771

  • Wong LH, Krauer KG, Hatzinisiriou I, Estcourt MJ, Hersey P, Tam ND, Edmondson S, Devenish RJ, Ralph SJ . 1997 J. Biol. Chem. 272: 28779–28785

  • Yan PS, Chen CM, Shi H, Rahmatpanah F, Wei SH, Caldwell CW, Huang TH . 2001 Cancer Res. 61: 8375–8380

  • Yan PS, Perry MR, Laux DE, Asare AL, Caldwell CW, Huang TH . 2000 Clin. Cancer Res. 6: 1432–1438

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Acknowledgements

We would like to thank the members of the Jones laboratory for valuable discussions and C Jette, B Karpf, B Moore and P Moos for critical reading of the manuscript. AR Karpf is a recipient of postdoctoral fellowship PF-99-151-01-CDD from the American Cancer Society. This work was supported by NIH P01-CA73992 (to DA Jones) and by the Huntsman Cancer Foundation.

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Correspondence to Adam R Karpf or David A Jones.

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Karpf, A., Jones, D. Reactivating the expression of methylation silenced genes in human cancer. Oncogene 21, 5496–5503 (2002). https://doi.org/10.1038/sj.onc.1205602

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