Journal of Molecular Medicine

, Volume 90, Issue 7, pp 791–801 | Cite as

The role of epigenetic regulation in stem cell and cancer biology

  • Lilian E. van Vlerken
  • Elaine M. Hurt
  • Robert E. Hollingsworth


Normal development and homeostasis requires a carefully coordinated gene expression program. Appropriate transcriptional regulation is maintained, in part, through epigenetic modifications of both DNA and histones. It is now apparent that the epigenetic landscape is complex and carefully controlled to both silence and activate gene transcription and that these states remain exquisitely poised for reversal. The deregulation of epigenetics in cancer is common and results in both the activation of oncogenes and the silencing of tumor suppressors. A tremendous amount of research corroborates the existence in many tumor types of a cancer stem cell that is both the origin and cell type responsible for resistance of tumors to current therapies. As our understanding of cancer stem cell biology continues, it is apparent that these cells are also under the influence of epigenetic regulation. We will discuss the cancer stem cell hypothesis and the role of epigenetics in both normal and cancer stem cell biology.


Cancer stem cells Polycomb repressive complex Histone modifications DNA methylation 


  1. 1.
    Dalerba P, Cho RW, Clarke MF (2007) Cancer stem cells: models and concepts. Annu Rev Med 58:267–284PubMedCrossRefGoogle Scholar
  2. 2.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 7:730–737CrossRefGoogle Scholar
  3. 3.
    Hope KJ, Jin L, Dick JE (2004) Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 5:738–743PubMedCrossRefGoogle Scholar
  4. 4.
    Wang JCY, Dick JE (2005) Cancer stem cells: lessons from leukemia. Trends Cell Biol 15:494–501PubMedCrossRefGoogle Scholar
  5. 5.
    Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CHM, Jones DL, Visvader J, Weissman IL, Wahl GM (2006) Cancer stem cells: perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res 66:9339–9344PubMedCrossRefGoogle Scholar
  6. 6.
    Johnsen HE, Kjeldsen MK, Urup T, Fogd K, Pilgaard L, Boegsted M, Nyegaard M, Christiansen I, Bukh A, Dybkaer K (2009) Cancer stem cells and the cellular hierarchy in haematological malignancies. Eur J Cancer 45(Supplement 1):194–201PubMedCrossRefGoogle Scholar
  7. 7.
    Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci 100:3983–3988PubMedCrossRefGoogle Scholar
  8. 8.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401PubMedCrossRefGoogle Scholar
  9. 9.
    Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65:10946–10951PubMedCrossRefGoogle Scholar
  10. 10.
    Ho MM, Ng AV, Lam S, Hung JY (2007) Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res 67:4827–4833PubMedCrossRefGoogle Scholar
  11. 11.
    Ma S, Chan KW, Hu L, Lee TKW, Wo JYH, Ng IOL, Zheng BJ, Guan XY (2007) Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132:2542–2556PubMedCrossRefGoogle Scholar
  12. 12.
    Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115PubMedCrossRefGoogle Scholar
  13. 13.
    Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037PubMedCrossRefGoogle Scholar
  14. 14.
    Bapat SA, Mali AM, Koppikar CB, Kurrey NK (2005) Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res 65:3025–3029PubMedGoogle Scholar
  15. 15.
    Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci 104:973–978PubMedCrossRefGoogle Scholar
  16. 16.
    Todaro M, Francipane MG, Medema JP, Stassi G (2010) Colon cancer stem cells: promise of targeted therapy. Gastroenterology 138:2151–2162PubMedCrossRefGoogle Scholar
  17. 17.
    Alison MR, Lim SML, Nicholson LJ (2011) Cancer stem cells: problems for therapy? J Pathol 223:148–162CrossRefGoogle Scholar
  18. 18.
    Dieter Sebastian M, Ball Claudia R, Hoffmann Christopher M, Nowrouzi A, Herbst F, Zavidij O, Abel U, Arens A, Weichert W, Brand K et al (2011) Distinct types of tumor-initiating cells form human colon cancer tumors and metastases. Cell Stem Cell 9:357–365PubMedCrossRefGoogle Scholar
  19. 19.
    Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P, Metzeler KH, Poeppl A, Ling V, Beyene J et al (2011) Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med 17:1086–1093PubMedCrossRefGoogle Scholar
  20. 20.
    Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu M-F, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC et al (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100:672–679PubMedCrossRefGoogle Scholar
  21. 21.
    Pajonk F, Vlashi E, McBride WH (2010) Radiation resistance of cancer stem cells: the 4 R's of radiobiology revisited. Stem Cells 28:639–648PubMedCrossRefGoogle Scholar
  22. 22.
    Moncharmont C, Levy A, Gilormini M, Bertrand G, Chargari C, Alphonse G, Ardail D, Rodriguez-Lafrasse C, Magne N (2012) Targeting a cornerstone of radiation resistance: cancer stem cell. Cancer Lett (in press)Google Scholar
  23. 23.
    Cho YM, Kim YS, Kang MJ, Farrar WL, Hurt EM (2012) Long-term recovery of irradiated prostate cancer increases cancer stem cells. Prostate. doi:10.1002/pros.22527
  24. 24.
    Koch U, Krause M, Baumann M (2010) Cancer stem cells at the crossroads of current cancer therapy failures—radiation oncology perspective. Semin Cancer Biol 20:116–124PubMedCrossRefGoogle Scholar
  25. 25.
    Phillips TM, McBride WH, Pajonk F (2006) The response of CD24-/low/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98:1777–1785PubMedCrossRefGoogle Scholar
  26. 26.
    Yin H, Glass J (2011) The phenotypic radiation resistance of CD44+/CD24-or low breast cancer cells is mediated through the enhanced activation of ATM signaling. PLoS One. doi:10.1371/journal.pone.0024080
  27. 27.
    Maugeri-Sacca M, Vigneri P, De Maria R (2011) Cancer stem cells and chemosensitivity. Clin Cancer Res 17:4942–4947PubMedCrossRefGoogle Scholar
  28. 28.
    Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, Pilozzi E, Larocca LM, Peschle C, De Maria R (2006) Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ 13:1238–1241PubMedCrossRefGoogle Scholar
  29. 29.
    Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, Conticello C, Ruco L, Peschle C, De Maria R (2007) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15:504–514PubMedCrossRefGoogle Scholar
  30. 30.
    Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY (2007) CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27:1749–1758PubMedCrossRefGoogle Scholar
  31. 31.
    Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, Lichter P, Unterberg A, Radlwimmer B, Herold-Mende CC (2008) Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14:123–129PubMedCrossRefGoogle Scholar
  32. 32.
    Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, Datar RH, Cote RJ (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12:5615–5621PubMedCrossRefGoogle Scholar
  33. 33.
    Moitra K, Lou H, Dean M (2011) Multidrug efflux pumps and cancer stem cells: insights into multidrug resistance and therapeutic development. Clin Pharmacol Ther 89:491–502PubMedCrossRefGoogle Scholar
  34. 34.
    Chapuy B, Koch R, Radunski U, Corsham S, Cheong N, Inagaki N, Ban N, Wenzel D, Reinhardt D, Zapf A et al (2008) Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration. Leukemia 22:1576–1586PubMedCrossRefGoogle Scholar
  35. 35.
    Cheng L, Wu Q, Huang Z, Guryanova OA, Huang Q, Shou W, Rich JN, Bao S (2011) L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1. EMBO J 30:800–813PubMedCrossRefGoogle Scholar
  36. 36.
    Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760PubMedCrossRefGoogle Scholar
  37. 37.
    Mathews LA, Cabarcas SM, Hurt EM, Zhang X, Jaffee EM, Farrar WL (2011) Increased expression of DNA repair genes in invasive human pancreatic cancer cells. Pancreas 40:730–739PubMedCrossRefGoogle Scholar
  38. 38.
    Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K, Holland EC (2008) PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 22:436–448PubMedCrossRefGoogle Scholar
  39. 39.
    Hua S, Xiaotao X, Renhua G, Yongmei Y, Lianke L, Wen G, Yongqian S (2012) Reduced miR–31 and let-7 maintain the balance between differentiation and quiescence in lung cancer stem-like side population cells. Biomed Pharmacother 66:89–97PubMedCrossRefGoogle Scholar
  40. 40.
    Xin H-W, Hari DM, Mullinax JE, Ambe CM, Koizumi T, Ray S, Anderson AJ, Wiegand GW, Garfield SH, Thorgeirsson SS et al (2012) Tumor-initiating label-retaining cancer cells in human gastrointestinal cancers undergo asymmetric cell division. Stem Cells 30:591–598PubMedCrossRefGoogle Scholar
  41. 41.
    Deleyrolle LP, Harding A, Cato K, Siebzehnrubl FA, Rahman M, Azari H, Olson S, Gabrielli B, Osborne G, Vescovi A et al (2011) Evidence for label-retaining tumour-initiating cells in human glioblastoma. Brain 134:1331–1343PubMedCrossRefGoogle Scholar
  42. 42.
    Klarmann G, Hurt E, Mathews L, Zhang X, Duhagon M, Mistree T, Thomas S, Farrar W (2009) Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature. Clin Exp Metastasis 26:433–446PubMedCrossRefGoogle Scholar
  43. 43.
    Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M et al (2008) The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715PubMedCrossRefGoogle Scholar
  44. 44.
    Ksia Zkiewicz M, Markiewicz A, Zaczek AJ (2012) Epithelial–mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells. Pathobiology 79:195–208CrossRefGoogle Scholar
  45. 45.
    Li L, Neaves WB (2006) Normal stem cells and cancer stem cells: the niche matters. Cancer Res 66:4553–4557PubMedCrossRefGoogle Scholar
  46. 46.
    Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111PubMedCrossRefGoogle Scholar
  47. 47.
    Harris PJ, Speranza G, Dansky Ullmann C (2012) Targeting embryonic signaling pathways in cancer therapy. Expert Opin Ther Targets 16:131–145PubMedCrossRefGoogle Scholar
  48. 48.
    Takebe N, Ivy SP (2010) Controversies in cancer stem cells: targeting embryonic signaling pathways. Clin Cancer Res 16:3106–3112PubMedCrossRefGoogle Scholar
  49. 49.
    Lien W-H, Guo X, Polak L, Lawton Lee N, Young Richard A, Zheng D, Fuchs E (2011) Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage. Cell Stem Cell 9:219–232PubMedCrossRefGoogle Scholar
  50. 50.
    O'Loghlen A, Munoz-Cabello Ana M, Gaspar-Maia A, Wu H-A, Banito A, Kunowska N, Racek T, Pemberton Helena N, Beolchi P, Lavial F et al (2012) MicroRNA regulation of Cbx7 mediates a switch of polycomb orthologs during ESC differentiation. Cell Stem Cell 10:33–46PubMedCrossRefGoogle Scholar
  51. 51.
    Richly H, Aloia L, Di Croce L (2011) Roles of the polycomb group proteins in stem cells and cancer. Cell Death Dis 2:e204PubMedCrossRefGoogle Scholar
  52. 52.
    Chou R-H, Yu Y-L, Hung M-C (2011) The roles of EZH2 in cell lineage commitment. Am J Transl Res 3:243–250PubMedGoogle Scholar
  53. 53.
    Chang CJ, Hung MC (2012) The role of EZH2 in tumour progression. Br J Cancer 106:243–247PubMedCrossRefGoogle Scholar
  54. 54.
    Crea F, Hurt E, Mathews L, Cabarcas S, Sun L, Marquez V, Danesi R, Farrar W (2011) Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancer. Molec Cancer 10:40CrossRefGoogle Scholar
  55. 55.
    Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257PubMedCrossRefGoogle Scholar
  56. 56.
    Fatemi M, Pao MM, Jeong S, Gal-Yam EN, Egger G, Weisenberger DJ, Jones PA (2005) Footprinting of mammalian promoters: use of a CpG DNA methyltransferase revealing nucleosome positions at a single molecule level. Nucleic Acids Res 33:e176PubMedCrossRefGoogle Scholar
  57. 57.
    Bock C, Jr W, Paulsen M, Lengauer T (2007) CpG island mapping by epigenome prediction. PLoS Comput Biol 3:e110PubMedCrossRefGoogle Scholar
  58. 58.
    Reik W (2007) Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447:425–432PubMedCrossRefGoogle Scholar
  59. 59.
    Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR (2003) TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia 17:637–641PubMedCrossRefGoogle Scholar
  60. 60.
    Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L et al (2009) Conversion of 5-methylcytosine to 5-Hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935PubMedCrossRefGoogle Scholar
  61. 61.
    Liutkeviciute Z, Lukinavicius G, Masevicius V, Daujotyte D, Klimasauskas S (2009) Cytosine-5-methyltransferases add aldehydes to DNA. Nat Chem Biol 5:400–402PubMedCrossRefGoogle Scholar
  62. 62.
    Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM (2010) Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463:1042–1047PubMedCrossRefGoogle Scholar
  63. 63.
    Rai K, Huggins IJ, James SR, Karpf AR, Jones DA, Cairns BR (2008) DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and Gadd45. Cell 135:1201–1212PubMedCrossRefGoogle Scholar
  64. 64.
    Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG (2001) Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet 10:687–692PubMedCrossRefGoogle Scholar
  65. 65.
    Watanabe Y, Maekawa M, Gregory SM (2010) Chapter 7—methylation of DNA in cancer. Adv Clin Chem 52:145–167PubMedCrossRefGoogle Scholar
  66. 66.
    Deneberg S, Guardiola P, Lennartsson A, Qu Y, Gaidzik V, Blanchet O, Karimi M, Bengtzen S, Nahi H, Uggla B et al (2011) Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks. Blood 118:5573–5582PubMedCrossRefGoogle Scholar
  67. 67.
    Kornberg RD, Lorch Y (1999) Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 98:285–294PubMedCrossRefGoogle Scholar
  68. 68.
    Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31:27–36PubMedCrossRefGoogle Scholar
  69. 69.
    Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45PubMedCrossRefGoogle Scholar
  70. 70.
    Tony K (2007) Chromatin modifications and their function. Cell 128:693–705CrossRefGoogle Scholar
  71. 71.
    Santos-Rosa H, Caldas C (2005) Chromatin modifier enzymes, the histone code and cancer. Eur J Cancer 41:2381–2402PubMedCrossRefGoogle Scholar
  72. 72.
    Di Lorenzo A, Bedford MT (2011) Histone arginine methylation. FEBS Lett 585:2024–2031PubMedCrossRefGoogle Scholar
  73. 73.
    Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6:838–849PubMedCrossRefGoogle Scholar
  74. 74.
    Ellis L, Atadja PW, Johnstone RW (2009) Epigenetics in cancer: targeting chromatin modifications. Mol Cancer Ther 8:1409–1420PubMedCrossRefGoogle Scholar
  75. 75.
    Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G (2007) Genome regulation by polycomb and trithorax proteins. Cell 128:735–745PubMedCrossRefGoogle Scholar
  76. 76.
    Pietersen AM, van Lohuizen M (2008) Stem cell regulation by polycomb repressors: postponing commitment. Curr Opin Cell Biol 20:201–207PubMedCrossRefGoogle Scholar
  77. 77.
    Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H et al (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16:1779–1791PubMedCrossRefGoogle Scholar
  78. 78.
    Buchwald G, van der Stoop P, Weichenrieder O, Perrakis A, van Lohuizen M, Sixma TK (2006) Structure and E3-ligase activity of the Ring–Ring complex of polycomb proteins Bmi1 and Ring1b. EMBO J 25:2465–2474PubMedCrossRefGoogle Scholar
  79. 79.
    Tachibana M, Matsumura Y, Fukuda M, Kimura H, Shinkai Y (2008) G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. EMBO J 27:2681–2690PubMedCrossRefGoogle Scholar
  80. 80.
    Guccione E, Bassi C, Casadio F, Martinato F, Cesaroni M, Schuchlautz H, Luscher B, Amati B (2007) Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive. Nature 449:933–937PubMedCrossRefGoogle Scholar
  81. 81.
    Yuan W, Xu M, Huang C, Liu N, Chen S, Zhu B (2011) H3K36 methylation antagonizes PRC2-mediated H3K27 methylation. J Biol Chem 286:7983–7989PubMedCrossRefGoogle Scholar
  82. 82.
    Nguyen AT, Taranova O, He J, Zhang Y (2011) DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. Blood 117:6912–6922PubMedCrossRefGoogle Scholar
  83. 83.
    Kim W, Kim R, Park G, Park J-W, Kim J-E (2011) The deficiency of H3K79 histone methyltransferase DOT1L inhibits cell proliferation. J Biol Chem. doi:10.1074/jbc.M1111.328138
  84. 84.
    Kilkenny ML, Dore AS, Roe SM, Nestoras K, Ho JCY, Watts FZ, Pearl LH (2008) Structural and functional analysis of the Crb2-BRCT2 domain reveals distinct roles in checkpoint signaling and DNA damage repair. Genes Dev 22:2034–2047PubMedCrossRefGoogle Scholar
  85. 85.
    Van Den Broeck A, Brambilla E, Moro-Sibilot D, Lantuejoul S, Brambilla C, Eymin B, Khochbin S, Gazzeri S (2008) Loss of histone H4K20 trimethylation occurs in preneoplasia and influences prognosis of non-small cell lung cancer. Clin Cancer Res 14:7237–7245CrossRefGoogle Scholar
  86. 86.
    Pedersen MT, Helin K (2010) Histone demethylases in development and disease. Trends Cell Biol 20:662–671PubMedCrossRefGoogle Scholar
  87. 87.
    Ciccone DN, Su H, Hevi S, Gay F, Lei H, Bajko J, Xu G, Li E, Chen T (2009) KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature 461:415–418PubMedCrossRefGoogle Scholar
  88. 88.
    Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AHFM, Gunther T, Buettner R, Schule R (2005) LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437:436–439PubMedGoogle Scholar
  89. 89.
    Xiang Y, Zhu Z, Han G, Lin H, Xu L, Chen CD (2007) JMJD3 is a histone H3K27 demethylase. Cell Res 17:850–857PubMedCrossRefGoogle Scholar
  90. 90.
    Seward DJ, Cubberley G, Kim S, Schonewald M, Zhang L, Tripet B, Bentley DL (2007) Demethylation of trimethylated histone H3 Lys4 in vivo by JARID1 JmjC proteins. Nat Struct Mol Biol 14:240–242PubMedCrossRefGoogle Scholar
  91. 91.
    Hong S, Cho Y-W, Yu L-R, Yu H, Veenstra TD, Ge K (2007) Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci 104:18439–18444PubMedCrossRefGoogle Scholar
  92. 92.
    Oncomine (2012) Available at
  93. 93.
    Shukla V, Vaissiere T, Herceg Z (2008) Histone acetylation and chromatin signature in stem cell identity and cancer. Mutat Res 637:1–15PubMedGoogle Scholar
  94. 94.
    Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K et al (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400PubMedCrossRefGoogle Scholar
  95. 95.
    Das C, Lucia MS, Hansen KC, Tyler JK (2009) CBP/p300-mediated acetylation of histone H3 on lysine 56. Nature 459:113–117PubMedCrossRefGoogle Scholar
  96. 96.
    Seligson DB, Horvath S, McBrian MA, Mah V, Yu H, Tze S, Wang Q, Chia D, Goodglick L, Kurdistani SK (2009) Global levels of histone modifications predict prognosis in different cancers. Am J Pathol 174:1619–1628PubMedCrossRefGoogle Scholar
  97. 97.
    Park J-A, Kim A-J, Kang Y, Jung Y-J, Kim H, Kim K-C (2011) Deacetylation and methylation at histone H3 lysine 9 (H3K9) coordinate chromosome condensation during cell cycle progression. Mol Cells 31:343–349PubMedCrossRefGoogle Scholar
  98. 98.
    Pasini D, Malatesta M, Jung HR, Walfridsson J, Willer A, Olsson L, Skotte J, Wutz A, Porse B, Jensen ONR et al (2010) Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of polycomb group target genes. Nucl Acids Res 38:4958–4969PubMedCrossRefGoogle Scholar
  99. 99.
    Ropero S, Esteller M (2007) The role of histone deacetylases (HDACs) in human cancer. Mol Oncol 1:19–25PubMedCrossRefGoogle Scholar
  100. 100.
    Glozak MA, Sengupta N, Zhang X, Seto E (2005) Acetylation and deacetylation of non-histone proteins. Gene 363:15–23PubMedCrossRefGoogle Scholar
  101. 101.
    Ma P, Pan H, Montgomery RL, Olson EN, Schultz RM (2012) Compensatory functions of histone deacetylase 1 (HDAC1) and HDAC2 regulate transcription and apoptosis during mouse oocyte development. Proc Natl Acad Sci. doi:10.1073/pnas.1118403109
  102. 102.
    Challen GA, Sun D, Jeong M, Luo M, Jelinek J, Berg JS, Bock C, Vasanthakumar A, Gu H, Xi Y et al (2011) Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44:23–31PubMedCrossRefGoogle Scholar
  103. 103.
    Hattori N, Imao Y, Nishino K, Hattori N, Ohgane J, Yagi S, Tanaka S, Shiota K (2007) Epigenetic regulation of Nanog gene in embryonic stem and trophoblast stem cells. Genes Cells 12:387–396PubMedCrossRefGoogle Scholar
  104. 104.
    Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R, Takahashi K, Okochi H, Okuda A, Matoba R, Sharov AA et al (2007) Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol 9:625–635PubMedCrossRefGoogle Scholar
  105. 105.
    Rodda DJ, Chew J-L, Lim L-H, Loh Y-H, Wang B, Ng H-H, Robson P (2005) Transcriptional regulation of Nanog by OCT4 and SOX2. J Biol Chem 280:24731–24737PubMedCrossRefGoogle Scholar
  106. 106.
    Wang K, Sengupta S, Magnani L, Wilson CA, Henry RW, Knott JG (2010) Brg1 is required for Cdx2-mediated repression of Oct4 expression in mouse blastocysts. PLoS One 5:e10622PubMedCrossRefGoogle Scholar
  107. 107.
    Leis O, Eguiara A, Lopez-Arribillaga E, Alberdi MJ, Hernandez-Garcia S, Elorriaga K, Pandiella A, Rezola R, Martin AG (2011) Sox2 expression in breast tumours and activation in breast cancer stem cells. Oncogene 31:1354–1365PubMedCrossRefGoogle Scholar
  108. 108.
    Guo Y, Liu S, Wang P, Zhao S, Wang F, Bing L, Zhang Y, Ling E-A, Gao J, Hao A (2011) Expression profile of embryonic stem cell-associated genes Oct4, Sox2 and Nanog in human gliomas. Histopathology 59:763–775PubMedCrossRefGoogle Scholar
  109. 109.
    Jeter CR, Liu B, Liu X, Chen X, Liu C, Calhoun-Davis T, Repass J, Zaehres H, Shen JJ, Tang DG (2011) NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene 30:3833–3845PubMedCrossRefGoogle Scholar
  110. 110.
    Leung EL-H, Fiscus RR, Tung JW, Tin VP-C, Cheng LC, Sihoe AD-L, Fink LM, Ma Y, Wong MP (2010) Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS One 5:e14062PubMedCrossRefGoogle Scholar
  111. 111.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedCrossRefGoogle Scholar
  112. 112.
    Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, Bernstein BE, Jaenisch R, Lander ES, Meissner A (2008) Dissecting direct reprogramming through integrative genomic analysis. Nature 454:49–55PubMedCrossRefGoogle Scholar
  113. 113.
    Pan G, Tian S, Nie J, Yang C, Ruotti V, Wei H, Jonsdottir GA, Stewart R, Thomson JA (2007) Whole-genome analysis of histone H3 Lysine 4 and lysine 27 methylation in human embryonic stem cells. Cell Stem Cell 1:299–312PubMedCrossRefGoogle Scholar
  114. 114.
    Sparmann A, van Lohuizen M (2006) Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 6:846–856PubMedCrossRefGoogle Scholar
  115. 115.
    Atkinson S, Armstrong L (2008) Epigenetics in embryonic stem cells: regulation of pluripotency and differentiation. Cell Tissue Res 331:23–29PubMedCrossRefGoogle Scholar
  116. 116.
    Rizzo SN, Hersey JM, Mellor P, Dai W, Santos-Silva A, Liber D, Luk L, Titley I, Carden CP, Box G et al (2011) Ovarian cancer stem cell-like side populations are enriched following chemotherapy and overexpress EZH2. Mol Cancer Ther 10:325–335PubMedCrossRefGoogle Scholar
  117. 117.
    Crea F, Hurt E, Farrar W (2010) Clinical significance of polycomb gene expression in brain tumors. Mol Cancer 9:265PubMedCrossRefGoogle Scholar
  118. 118.
    Facchino S, Abdouh M, Chatoo W, Bernier G (2010) BMI1 Confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. J Neurosci 30:10096–10111PubMedCrossRefGoogle Scholar
  119. 119.
    Hollier B, Evans K, Mani S (2009) The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia 14:29–43PubMedCrossRefGoogle Scholar
  120. 120.
    Yang M-H, Hsu DS-S, Wang H-W, Wang H-J, Lan H-Y, Yang W-H, Huang C-H, Kao S-Y, Tzeng C-H, Tai S-K et al (2010) Bmi1 is essential in Twist1-induced epithelial–mesenchymal transition. Nat Cell Biol 12:982–992PubMedCrossRefGoogle Scholar
  121. 121.
    Abdouh M, Facchino S, Chatoo W, Balasingam V, Ferreira J, Bernier G (2009) BMI1 sustains human glioblastoma multiforme stem cell renewal. J Neurosci 29:8884–8896PubMedCrossRefGoogle Scholar
  122. 122.
    Wang J, Lu F, Ren Q, Sun H, Xu Z, Lan R, Liu Y, Ward D, Quan J, Ye T et al (2011) Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res 71:7238–7249PubMedCrossRefGoogle Scholar
  123. 123.
    Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RKM, Tan PBO, Liu ET, Yu Q (2007) Pharmacologic disruption of polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 21:1050–1063PubMedCrossRefGoogle Scholar
  124. 124.
    Zhou J, Bi C, Cheong L-L, Mahara S, Liu S-C, Tay K-G, Koh T-L, Yu Q, Chng W-J (2011) The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML. Blood 118:2830–2839PubMedCrossRefGoogle Scholar
  125. 125.
    Chiba T, Suzuki E, Negishi M, Saraya A, Miyagi S, Konuma T, Tanaka S, Tada M, Kanai F, Imazeki F et al (2011) 3-deazaneplanocin A is a promising therapeutic agent for the eradication of tumor-initiating hepatocellular carcinoma cells. Int J Cancer 130:2557–2567PubMedCrossRefGoogle Scholar
  126. 126.
    Suva M-L, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle J-C, Baumer K, Le Bitoux M-A, Marino D, Cironi L et al (2009) EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res 69:9211–9218PubMedCrossRefGoogle Scholar
  127. 127.
    Miranda TB, Cortez CC, Yoo CB, Liang G, Abe M, Kelly TK, Marquez VE, Jones PA (2009) DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther 8:1579–1588PubMedCrossRefGoogle Scholar
  128. 128.
    Coulombe R, Sharma R, Huggins J (1995) Pharmacokinetics of the antiviral agent 3-deazaneplanocin A. Eur J Drug Metab Pharmacokinet 20:197–202PubMedCrossRefGoogle Scholar
  129. 129.
    Crea F, Paolicchi E, Marquez VE, Danesi R (2011) Polycomb genes and cancer: time for clinical application? Crit Rev Oncol Hematol. doi:10.1016/j.critrevonc.2011.1010.1007
  130. 130.
    Simon C, Chagraoui J, Krosl J, Gendron P, Wilhelm B, Lemieux S, Boucher G, Chagnon P, Drouin S, Lambert R et al (2012) A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev 26:651–656PubMedCrossRefGoogle Scholar
  131. 131.
    Nalls D, Tang S-N, Rodova M, Srivastava RK, Shankar S (2011) Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. PLoS One 6:e24099PubMedCrossRefGoogle Scholar
  132. 132.
    Baba T, Convery PA, Matsumura N, Whitaker RS, Kondoh E, Perry T, Huang Z, Bentley RC, Mori S, Fujii S et al (2008) Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene 28:209–218PubMedCrossRefGoogle Scholar
  133. 133.
    Tabu K, Sasai K, Kimura T, Wang L, Aoyanagi E, Kohsaka S, Tanino M, Nishihara H, Tanaka S (2008) Promoter hypomethylation regulates CD133 expression in human gliomas. Cell Res 18:1037–1046PubMedCrossRefGoogle Scholar
  134. 134.
    Yi JM, Tsai H-C, Glockner SC, Lin S, Ohm JE, Easwaran H, James CD, Costello JF, Riggins G, Eberhart CG et al (2008) Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors. Cancer Res 68:8094–8103PubMedCrossRefGoogle Scholar
  135. 135.
    You H, Ding W, Rountree CB (2010) Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-β. Hepatology 51:1635–1644PubMedCrossRefGoogle Scholar
  136. 136.
    de Sousa E, Melo F, Colak S, Buikhuisen J, Koster J, Cameron K, de Jong JH, Tuynman JB, Prasetyanti PR, Fessler E et al (2011) Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients. Cell Stem Cell 9:476–485CrossRefGoogle Scholar
  137. 137.
    Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, Danenberg E, Clarke AR, Sansom OJ, Clevers H (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457:608–611PubMedCrossRefGoogle Scholar
  138. 138.
    Alva AS, Hahn NM, Aparicio AM, Singal R, Yellapragada S, Sonpavde G (2011) Hypomethylating agents for urologic cancers. Future Oncol 7:447–463PubMedCrossRefGoogle Scholar
  139. 139.
    Fouse SD, Shen Y, Pellegrini M, Cole S, Meissner A, Van Neste L, Jaenisch R, Fan G (2008) Promoter CpG methylation contributes to es cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell 2:160–169PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Lilian E. van Vlerken
    • 1
  • Elaine M. Hurt
    • 1
  • Robert E. Hollingsworth
    • 1
  1. 1.Oncology ResearchMedImmune, LLC, One MedImmune WayGaithersburgUSA

Personalised recommendations