Ovarian Cancer pp 131-146 | Cite as

Epigenetics and Ovarian Cancer

  • Kenneth P. Nephew
  • Curt Balch
  • Shu Zhang
  • Tim H-M. Huang
Part of the Cancer Treatment and Research book series (CTAR, volume 149)

Cancer Epigenetics: Introduction

Epigenetics is a broad term that refers to all stably heritable alterations in gene expression that occur without changes in DNA base sequence. Epigenetic phenomena include deoxycytosine methylation, histone protein modifications, nucleosome position effects on DNA, and gene regulation by noncoding RNA molecules (Fig. 6.1); the overall epigenetic state corresponding with a specific cell phenotype is referred to as an “epigenome.” The Human Genome Project, completed in 2003, has provided a wealth of data regarding the relationship of DNA sequence to human health, and one interesting outcome of that project was the observation that humans possess far fewer genes than previously predicted. 1That vast underestimation of human genes suggested a much greater role for phenotype-specific gene regulation by other mechanisms, including epigenetic modifications. Consequently, a Human Epigenome Project, an international public/private consortium, has now been...


Ovarian Cancer Ovarian Cancer Cell Ovarian Tumor Ovarian Cancer Cell Line H3K27 Trimethylation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors gratefully acknowledge grant support from the U.S. National Institutes of Health, National Cancer Institute grants CA085289 (to K.P.N.), CA113001 (to T. T-H. H), Ovar'coming Together (Indianapolis, IN, to C.B.), the Walther Cancer Institute (Indianapolis, IN, to K.P.N.), and Phi Beta Psi Sorority (Brownsburg, IN, to K.P.N.)


  1. 1.
    International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431:931–945.Google Scholar
  2. 2.
    Garber K. Momentum building for human epigenome project. J Natl Cancer Inst. 2006;98:84–86.PubMedCrossRefGoogle Scholar
  3. 3.
    Jones P. A. DNA methylation and cancer. Oncogene. 2002;21:5358–5360.PubMedCrossRefGoogle Scholar
  4. 4.
    Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res. 1998;72:141–196.PubMedCrossRefGoogle Scholar
  5. 5.
    Bestor TH. The host defence function of genomic methylation patterns. Novartis Found Symp. 1998;214:187–195; discussion 195–189, 228–132.PubMedGoogle Scholar
  6. 6.
    Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148–1159.PubMedCrossRefGoogle Scholar
  7. 7.
    Fahrner JA, Eguchi S, Herman JG, Baylin SB. Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res. 2002;62:7213–7218.PubMedGoogle Scholar
  8. 8.
    Balch C, Huang TH, Brown R, Nephew KP. The epigenetics of ovarian cancer drug resistance and resensitization. Am J Obstet Gynecol. 2004;191:1552–1572.PubMedCrossRefGoogle Scholar
  9. 9.
    Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128:669–681.PubMedCrossRefGoogle Scholar
  10. 10.
    Turner BM. Cellular memory and the histone code. Cell. 2002;111:285–291.PubMedCrossRefGoogle Scholar
  11. 11.
    Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8:286–298.PubMedCrossRefGoogle Scholar
  12. 12.
    Luscher-Firzlaff J, Gawlista I, Vervoorts J, et al. The human trithorax protein hASH2 functions as an oncoprotein. Cancer Res. 2008;68:749–758.PubMedCrossRefGoogle Scholar
  13. 13.
    Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006;6:846–856.PubMedCrossRefGoogle Scholar
  14. 14.
    Bernstein BE, Mikkelsen TS, Xie X, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125:315–326.PubMedCrossRefGoogle Scholar
  15. 15.
    Ohm JE, McGarvey KM, Yu X, et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet. 2007;39:237–242.PubMedCrossRefGoogle Scholar
  16. 16.
    Ohm JE, Baylin SB. Stem cell chromatin patterns: an instructive mechanism for DNA hypermethylation? Cell Cycle. 2007;6:1040–1043.PubMedGoogle Scholar
  17. 17.
    Balch C, Nephew KP, Huang TH, Bapat SA. Epigenetic “bivalently marked” process of cancer stem cell-driven tumorigenesis. Bioessays. 2007;29:842–845.PubMedCrossRefGoogle Scholar
  18. 18.
    Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet. 2006;7:21–33.PubMedCrossRefGoogle Scholar
  19. 19.
    Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355:1253–1261.PubMedCrossRefGoogle Scholar
  20. 20.
    Vignali M, Hassan AH, Neely KE, Workman JL. ATP-dependent chromatin-remodeling complexes. Mol Cell Biol. 2000;20:1899–1910.PubMedCrossRefGoogle Scholar
  21. 21.
    Roberts CW, Orkin SH. The SWI/SNF complex – chromatin and cancer. Nat Rev Cancer. 2004;4:133–142.PubMedGoogle Scholar
  22. 22.
    Srinivasan R, Mager GM, Ward RM, Mayer J, Svaren J. NAB2 represses transcription by interacting with the CHD4 subunit of the nucleosome remodeling and deacetylase (NuRD) complex. J Biol Chem. 2006;281:15129–15137.PubMedCrossRefGoogle Scholar
  23. 23.
    Cullen BR. Transcription and processing of human microRNA precursors. Mol Cell. 2004;16:861–865.PubMedCrossRefGoogle Scholar
  24. 24.
    Murphy D, Dancis B, Brown JR. The evolution of core proteins involved in microRNA biogenesis. BMC Evol Biol. 2008;8:92.PubMedCrossRefGoogle Scholar
  25. 25.
    Aravin AA, Hannon GJ, Brennecke J. The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race. Science. 2007;318:761–764.PubMedCrossRefGoogle Scholar
  26. 26.
    Seto AG, Kingston RE, Lau NC. The coming of age for Piwi proteins. Mol Cell. 2007;26:603–609.PubMedCrossRefGoogle Scholar
  27. 27.
    Stadler BM, Ruohola-Baker H. Small RNAs: keeping stem cells in line. Cell. 2008;132:563–566.PubMedCrossRefGoogle Scholar
  28. 28.
    Stefani G, Slack FJ. Small non-coding RNAs in animal development. Nat Rev Mol Cell Biol. 2008;9:219–230.PubMedCrossRefGoogle Scholar
  29. 29.
    Esquela-Kerscher A, Slack FJ. Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–269.PubMedCrossRefGoogle Scholar
  30. 30.
    American Cancer Society, Key Statistics About Ovarian Cancer. American Cancer Society Center, 250 Williams Street, Atlanta, GA, 2006.Google Scholar
  31. 31.
    Bast RC, Jr. Status of tumor markers in ovarian cancer screening. J Clin Oncol. 2003;21:200–205.CrossRefGoogle Scholar
  32. 32.
    Ozols RF. Systemic therapy for ovarian cancer: current status and new treatments. Semin Oncol. 2006;33:S3–11.PubMedCrossRefGoogle Scholar
  33. 33.
    Widschwendter M, Jiang G, Woods C, et al. DNA hypomethylation and ovarian cancer biology. Cancer Res. 2004;64:4472–4480.PubMedCrossRefGoogle Scholar
  34. 34.
    Pattamadilok J, Huapai N, Rattanatanyong P, et al. LINE-1 hypomethylation level as a potential prognostic factor for epithelial ovarian cancer. Int J Gynecol Cancer. 2007;18:711–7.Google Scholar
  35. 35.
    Leu YW, Rahmatpanah F, Shi H, et al. Double RNA interference of DNMT3b and DNMT1 enhances DNA demethylation and gene reactivation. Cancer Res. 2003;63:6110–6115.PubMedGoogle Scholar
  36. 36.
    Barton CA, Hacker NF, Clark SJ, O'Brien PM. DNA methylation changes in ovarian cancer: implications for early diagnosis, prognosis and treatment. Gynecol Oncol. 2008;109:129–139.PubMedCrossRefGoogle Scholar
  37. 37.
    Feng W, Marquez RT, Lu Z, et al. Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation. Cancer. 2008;112:1489–1502.PubMedCrossRefGoogle Scholar
  38. 38.
    Terasawa K, Sagae S, Toyota M, et al. Epigenetic inactivation of TMS1/ASC in ovarian cancer. Clin Cancer Res. 2004;10:2000–2006.PubMedCrossRefGoogle Scholar
  39. 39.
    Arnold JM, Cummings M, Purdie D, Chenevix-Trench G. Reduced expression of intercellular adhesion molecule-1 in ovarian adenocarcinomas. Br J Cancer. 2001;85:1351–1358.PubMedCrossRefGoogle Scholar
  40. 40.
    Sellar GC, Watt KP, Rabiasz GJ, et al. OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer. Nat Genet. 2003;34:337–343.PubMedCrossRefGoogle Scholar
  41. 41.
    Yuecheng Y, Hongmei L, Xiaoyan X. Clinical evaluation of E-cadherin expression and its regulation mechanism in epithelial ovarian cancer. Clin Exp Metastasis. 2006;23:65–74.PubMedCrossRefGoogle Scholar
  42. 42.
    Rong R, Jin W, Zhang J, Sheikh MS, Huang Y. Tumor suppressor RASSF1A is a microtubule-binding protein that stabilizes microtubules and induces G2/M arrest. Oncogene. 2004;23:8216–8230.PubMedCrossRefGoogle Scholar
  43. 43.
    Backen AC, Cole CL, Lau SC, et al. Heparan sulphate synthetic and editing enzymes in ovarian cancer. Br J Cancer. 2007;96:1544–1548.PubMedCrossRefGoogle Scholar
  44. 44.
    Staub J, Chien J, Pan Y, et al. Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance. Oncogene. 2007;26:4969–4978.PubMedCrossRefGoogle Scholar
  45. 45.
    Kurose K, Zhou XP, Araki T, Cannistra SA, Maher ER, Eng C. Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas. Am J Pathol. 2001;158:2097–2106.PubMedGoogle Scholar
  46. 46.
    Akahira J, Sugihashi Y, Suzuki T, et al. Decreased expression of 14-3-3 sigma is associated with advanced disease in human epithelial ovarian cancer: its correlation with aberrant DNA methylation. Clin Cancer Res. 2004;10:2687–2693.PubMedCrossRefGoogle Scholar
  47. 47.
    Hatle KM, Neveu W, Dienz O, et al. Methylation-controlled J protein promotes c-Jun degradation to prevent ABCB1 transporter expression. Mol Cell Biol. 2007;27:2952–2966.PubMedCrossRefGoogle Scholar
  48. 48.
    Shridhar V, Bible KC, Staub J, et al. Loss of expression of a new member of the DNAJ protein family confers resistance to chemotherapeutic agents used in the treatment of ovarian cancer. Cancer Res. 2001;61:4258–4265.PubMedGoogle Scholar
  49. 49.
    Gupta A, Godwin AK, Vanderveer L, Lu A, Liu J. Hypomethylation of the synuclein gamma gene CpG island promotes its aberrant expression in breast carcinoma and ovarian carcinoma. Cancer Res. 2003;63:664–673.PubMedGoogle Scholar
  50. 50.
    Litkouhi B, Kwong J, Lo CM, et al. Claudin-4 overexpression in epithelial ovarian cancer is associated with hypomethylation and is a potential target for modulation of tight junction barrier function using a C-terminal fragment of Clostridium perfringens enterotoxin. Neoplasia. 2007;9:304–314.PubMedCrossRefGoogle Scholar
  51. 51.
    Rose SL, Fitzgerald MP, White NO, et al. Epigenetic regulation of maspin expression in human ovarian carcinoma cells. Gynecol Oncol . 2006;102:319–324.PubMedCrossRefGoogle Scholar
  52. 52.
    Yao X, Hu JF, Li T, et al. Epigenetic regulation of the taxol resistance-associated gene TRAG-3 in human tumors. Cancer Genet Cytogenet. 2004;151:1–13.PubMedCrossRefGoogle Scholar
  53. 53.
    LaVoie HA. Epigenetic control of ovarian function: the emerging role of histone modifications. Mol Cell Endocrinol. 2005;243:12–18.PubMedCrossRefGoogle Scholar
  54. 54.
    Ozdag H, Teschendorff AE, Ahmed AA, et al. Differential expression of selected histone modifier genes in human solid cancers. BMC Genomics. 2006;7:90.PubMedCrossRefGoogle Scholar
  55. 55.
    Caslini C, Capo-chichi CD, Roland IH, Nicolas E, Yeung AT, Xu XX. Histone modifications silence the GATA transcription factor genes in ovarian cancer. Oncogene. 2006;25:5446–5461.PubMedCrossRefGoogle Scholar
  56. 56.
    Strait KA, Dabbas B, Hammond EH, Warnick CT, Iistrup SJ, Ford CD. Cell cycle blockade and differentiation of ovarian cancer cells by the histone deacetylase inhibitor trichostatin A are associated with changes in p21, Rb, and Id proteins. Mol Cancer Ther. 2002;1:1181–1190.PubMedGoogle Scholar
  57. 57.
    Abbosh PH, Montgomery JS, Starkey JA, et al. Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells. Cancer Res. 2006;66:5582–5591.PubMedCrossRefGoogle Scholar
  58. 58.
    Wei Y, Xia W, Zhang Z, et al. Loss of trimethylation at lysine 27 of histone H3 is a predictor of poor outcome in breast, ovarian, and pancreatic cancers. Mol Carcinog. 2008;47:701–6.Google Scholar
  59. 59.
    Shih Ie M, Sheu JJ, Santillan A, et al. Amplification of a chromatin remodeling gene, Rsf-1/HBXAP, in ovarian carcinoma. Proc Natl Acad Sci USA. 2005;102:14004–14009.PubMedCrossRefGoogle Scholar
  60. 60.
    Davidson B, Trope CG, Wang TL, Shih Ie M. Expression of the chromatin remodeling factor Rsf-1 is upregulated in ovarian carcinoma effusions and predicts poor survival. Gynecol Oncol. 2006;103:814–819.PubMedCrossRefGoogle Scholar
  61. 61.
    Nicolson GL, Nawa A, Toh Y, Taniguchi S, Nishimori K, Moustafa A. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation and nuclear regulation. Clin Exp Metastasis. 2003;20:19–24.PubMedCrossRefGoogle Scholar
  62. 62.
    Nawa A, Nishimori K, Lin P, et al. Tumor metastasis-associated human MTA1 gene: its deduced protein sequence, localization, and association with breast cancer cell proliferation using antisense phosphorothioate oligonucleotides. J Cell Biochem. 2000;79:202–212.PubMedCrossRefGoogle Scholar
  63. 63.
    Bochar DA, Wang L, Beniya H, et al. BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell. 2000;102:257–265.PubMedCrossRefGoogle Scholar
  64. 64.
    Glaros S, Cirrincione GM, Muchardt C, Kleer CG, Michael CW, Reisman D. The reversible epigenetic silencing of BRM: implications for clinical targeted therapy. Oncogene. 2007;26:7058–7066.PubMedCrossRefGoogle Scholar
  65. 65.
    Iorio MV, Visone R, Di Leva G, et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67:8699–8707.PubMedCrossRefGoogle Scholar
  66. 66.
    Yang H, Kong W, He L, et al. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res. 2008;68:425–433.PubMedCrossRefGoogle Scholar
  67. 67.
    Zhang L, Volinia S, Bonome T, et al. Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc Natl Acad Sci USA. 2008;105:7004–7009.PubMedCrossRefGoogle Scholar
  68. 68.
    Wei SH, Balch C, Paik HH, et al. Prognostic DNA methylation biomarkers in ovarian cancer. Clin Cancer Res. 2006;12:2788–2794.PubMedCrossRefGoogle Scholar
  69. 69.
    Muller HM, Millinger S, Fiegl H, et al. Analysis of methylated genes in peritoneal fluids of ovarian cancer patients: a new prognostic tool. Clin Chem. 2004;50:2171–2173.PubMedCrossRefGoogle Scholar
  70. 70.
    Chan MW, Wei SH, Wen P, et al. Hypermethylation of 18S and 28S ribosomal DNAs predicts progression-free survival in patients with ovarian cancer. Clin Cancer Res. 2005;11:7376–7383.PubMedCrossRefGoogle Scholar
  71. 71.
    Teodoridis JM, Hall J, Marsh S, et al. CpG island methylation of DNA damage response genes in advanced ovarian cancer. Cancer Res. 2005;65:8961–8967.PubMedCrossRefGoogle Scholar
  72. 72.
    Makarla PB, Saboorian MH, Ashfaq R, et al. Promoter hypermethylation profile of ovarian epithelial neoplasms. Clin Cancer Res. 2005;11:5365–5369.PubMedCrossRefGoogle Scholar
  73. 73.
    Okochi-Takada E, Nakazawa K, Wakabayashi M, et al. Silencing of the UCHL1 gene in human colorectal and ovarian cancers. Int J Cancer. 2006;119:1338–1344.PubMedCrossRefGoogle Scholar
  74. 74.
    Fiegl H, Windbichler G, Mueller-Holzner E, et al. HOXA11 DNA methylation-A novel prognostic biomarker in ovarian cancer. Int J Cancer. 2008;123:729–9.Google Scholar
  75. 75.
    Gifford G, Paul J, Vasey PA, Kaye SB, Brown R. The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients. Clin Cancer Res. 2004;10:4420–4426.PubMedCrossRefGoogle Scholar
  76. 76.
    Ibanez de Caceres I, Battagli C, Esteller M, et al. Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Cancer Res. 2004;64:6476–6481.PubMedCrossRefGoogle Scholar
  77. 77.
    Ransohoff DF. Lessons from controversy: ovarian cancer screening and serum proteomics. J Natl Cancer Inst. 2005;97:315–319.PubMedCrossRefGoogle Scholar
  78. 78.
    Rosenthal AN, Menon U, Jacobs IJ. Screening for ovarian cancer. Clin Obstet Gynecol . 2006;49:433–447.PubMedCrossRefGoogle Scholar
  79. 79.
    Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med. 2001;134:573–586.PubMedGoogle Scholar
  80. 80.
    Goffin J, Eisenhauer E. DNA methyltransferase inhibitors-state of the art. Ann Oncol. 2002;13:1699–1716.PubMedCrossRefGoogle Scholar
  81. 81.
    Kaminskas E, Farrell A, Abraham S, et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res. 2005;11:3604–3608.PubMedCrossRefGoogle Scholar
  82. 82.
    Issa JP. Decitabine. Curr Opin Oncol. 2003;15:446–451.PubMedCrossRefGoogle Scholar
  83. 83.
    Sasaki M, Kaneuchi M, Fujimoto S, Tanaka Y, Dahiya R. Hypermethylation can selectively silence multiple promoters of steroid receptors in cancers. Mol Cell Endocrinol. 2003;202:201–207.PubMedGoogle Scholar
  84. 84.
    Nguyen CT, Weisenberger DJ, Velicescu M, et al. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'-deoxycytidine. Cancer Res. 2002;62:6456–6461.PubMedGoogle Scholar
  85. 85.
    Balch C, Yan P, Craft T, et al. Antimitogenic and chemosensitizing effects of the methylation inhibitor zebularine in ovarian cancer. Mol Cancer Ther. 2005;4:1505–1514.PubMedCrossRefGoogle Scholar
  86. 86.
    Yoo CB, Jeong S, Egger G, et al. Delivery of 5-aza-2'-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res. 2007;67:6400–6408.PubMedCrossRefGoogle Scholar
  87. 87.
    Lee WJ, Shim JY, Zhu BT. Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol Pharmacol. 2005;68:1018–1030.PubMedCrossRefGoogle Scholar
  88. 88.
    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;9:1596–1603.PubMedGoogle Scholar
  89. 89.
    Villar-Garea A, Fraga MF, Espada J, Esteller M. Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. Cancer Res. 2003;63:4984–4989.PubMedGoogle Scholar
  90. 90.
    Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer. 2001;1:194–202.PubMedCrossRefGoogle Scholar
  91. 91.
    Zeng L, Zhang Y, Chien S, Liu X, Shyy JY. The role of p53 deacetylation in p21Waf1 regulation by laminar flow. J Biol Chem. 2003;278:24594–24599.PubMedCrossRefGoogle Scholar
  92. 92.
    Blagosklonny MV, Robey R, Sackett DL, et al. Histone deacetylase inhibitors all induce p21 but differentially cause tubulin acetylation, mitotic arrest, and cytotoxicity. Mol Cancer Ther. 2002;1:937–941.PubMedGoogle Scholar
  93. 93.
    Takai N, Kawamata N, Gui D, Said JW, Miyakawa I, Koeffler HP. Human ovarian carcinoma cells: histone deacetylase inhibitors exhibit antiproliferative activity and potently induce apoptosis. Cancer. 2004;101:2760–2770.PubMedCrossRefGoogle Scholar
  94. 94.
    Modesitt SC, Sill M, Hoffman JS, Bender DP. A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2008;109:182–186.PubMedCrossRefGoogle Scholar
  95. 95.
    Plumb JA, Finn PW, Williams RJ, et al. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther. 2003;2:721–728.PubMedGoogle Scholar
  96. 96.
    Takai N, Ueda T, Nishida M, Nasu K, Narahara H. A novel histone deacetylase inhibitor, Scriptaid, induces growth inhibition, cell cycle arrest and apoptosis in human endometrial cancer and ovarian cancer cells. Int J Mol Med. 2006;17:323–329.PubMedGoogle Scholar
  97. 97.
    Arts J, Angibaud P, Marien A, et al. R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies. Br J Cancer. 2007;97:1344–1353.PubMedCrossRefGoogle Scholar
  98. 98.
    Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–692.PubMedCrossRefGoogle Scholar
  99. 99.
    Boyer LA, Plath K, Zeitlinger J, et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature. 2006;441:349–353.PubMedCrossRefGoogle Scholar
  100. 100.
    Bibikova M, Chudin E, Wu B, et al. Human embryonic stem cells have a unique epigenetic signature. Genome Res. 2006;16:1075–1083.PubMedCrossRefGoogle Scholar
  101. 101.
    Cooper AL, Greenberg VL, Lancaster PS, van Nagell JR Jr, Zimmer SG, Modesitt SC. In vitro and in vivo histone deacetylase inhibitor therapy with suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer. Gynecol Oncol. 2007;104:596–601.PubMedCrossRefGoogle Scholar
  102. 102.
    Sonnemann J, Gange J, Pilz S, Stotzer C, Ohlinger R, Belau A, Lorenz G, Beck JF. Comparative evaluation of the treatment efficacy of suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer cell lines and primary ovarian cancer cells from patients. BMC Cancer. 2006;6:183.PubMedCrossRefGoogle Scholar
  103. 103.
    Qian X, LaRochelle WJ, Ara G, et al. Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies. Mol Cancer Ther . 2006;5:2086–2095.PubMedCrossRefGoogle Scholar
  104. 104.
    Lin CT, Lai HC, Lee HY, et al. Valproic acid resensitizes cisplatin-resistant ovarian cancer cells. Cancer Sci. 2008;99:1218–1226.PubMedCrossRefGoogle Scholar
  105. 105.
    Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R. Reversal of drug resistance in human tumor xenografts by 2'-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res. 2000;60:6039–6044.PubMedGoogle Scholar
  106. 106.
    Strathdee G, MacKean MJ, Illand M, Brown R. A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer. Oncogene. 1999;18:2335–2341.PubMedCrossRefGoogle Scholar
  107. 107.
    Candelaria M, Gallardo-Rincon D, Arce C, et al. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann Oncol. 2007;18:1529–1538.PubMedCrossRefGoogle Scholar
  108. 108.
    Lau OD, Kundu TK, Soccio RE, et al. HATs off: selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF. Mol Cell. 2000;5:589–595.PubMedCrossRefGoogle Scholar
  109. 109.
    Sansom OJ, Maddison K, Clarke AR. Mechanisms of disease: methyl-binding domain proteins as potential therapeutic targets in cancer. Nat Clin Pract Oncol. 2007;4:305–315.PubMedCrossRefGoogle Scholar
  110. 110.
    Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006;20:1123–1136.PubMedCrossRefGoogle Scholar
  111. 111.
    O'Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T. The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol. 2001;21:4330–4336.PubMedCrossRefGoogle Scholar
  112. 112.
    Tan J, Yang X, Zhuang L, et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007;21:1050–1063.PubMedCrossRefGoogle Scholar
  113. 113.
    Zhang S, Balch C, Chan MW, et al. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res , 2008;68:4311–20.Google Scholar
  114. 114.
    Clarke MF, Dick JE, Dirks PB, et al. Cancer stem cells – perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006;66:9339–9344.PubMedCrossRefGoogle Scholar
  115. 115.
    Dalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts. Annu Rev Med. 2007;58:267–284.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Kenneth P. Nephew
    • 1
    • 2
  • Curt Balch
    • 1
  • Shu Zhang
    • 1
  • Tim H-M. Huang
    • 1
  1. 1.Medical SciencesIndiana UniversityBloomingtonUSA
  2. 2.Indiana University Cancer CenterIndianapolisUSA

Personalised recommendations