Skip to main content
SpringerLink
Log in

Epigenetic mechanisms of tumorigenicity manifesting in stem cells

  • Review
  • Published:
Oncogene Submit manuscript

Abstract

One of the biggest roadblocks to using stem cells as the basis for regenerative medicine therapies is the tumorigenicity of stem cells. Unfortunately, the unique abilities of stem cells to self-renew and differentiate into a variety of cell types are also mechanistically linked to their tumorigenic behaviors. Understanding the mechanisms underlying the close relationship between stem cells and cancer cells has therefore become a primary goal in the field. In addition, knowledge gained from investigating the striking parallels between mechanisms orchestrating normal embryogenesis and those that invoke tumorigenesis may well serve as the foundation for developing novel cancer treatments. Emerging discoveries have demonstrated that epigenetic regulatory machinery has important roles in normal stem cell functions, cancer development and cancer stem cell (CSC) identity. These studies provide valuable insights into both the shared and distinct mechanisms by which pluripotency and oncogenicity are established and regulated. In this review, the cancer-related epigenetic mechanisms found in pluripotent stem cells and cancer cells will be discussed, focusing on both the similarities and the differences.

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Hanahan D, Weinberg RA . The hallmarks of cancer. Cell 2000; 100: 57–70.

    Article  CAS  Google Scholar 

  2. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  Google Scholar 

  3. Stevens LC, Little CC . Spontaneous testicular teratomas in an inbred strain of mice. Proc Natl Acad Sci USA 1954; 40: 1080–1087.

    CAS  Google Scholar 

  4. Jacob F . The Leeuwenhoek Lecture, 1977. Mouse teratocarcinoma and mouse embryo. Proc R Soc Lond B Biol Sci 1978; 201: 249–270.

    CAS  Google Scholar 

  5. Solter D . From teratocarcinomas to embryonic stem cells and beyond: a history of embryonic stem cell research. Nat Rev Genet 2006; 7: 319–327.

    CAS  Google Scholar 

  6. Evans MJ, Kaufman MH . Establishment in culture of pluripotential cells from mouse embryos. Nature 1981; 292: 154–156.

    CAS  Google Scholar 

  7. Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, Draper JS . Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans 2005; 33: 1526–1530.

    CAS  Google Scholar 

  8. Greber B, Lehrach H, Adjaye J . Silencing of core transcription factors in human EC cells highlights the importance of autocrine FGF signaling for self-renewal. BMC Dev Biol 2007; 7: 46.

    Google Scholar 

  9. Jordan CT, Guzman ML, Noble M . Cancer stem cells. N Engl J Med 2006; 355: 1253–1261.

    CAS  Google Scholar 

  10. Dalerba P, Cho RW, Clarke MF . Cancer stem cells: models and concepts. Annu Rev Med 2007; 58: 267–284.

    Article  CAS  Google Scholar 

  11. Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737.

    Article  CAS  Google Scholar 

  12. Nguyen LV, Vanner R, Dirks P, Eaves CJ . Cancer stem cells: an evolving concept. Nat Rev Cancer 2012; 12: 133–143.

    CAS  Google Scholar 

  13. Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL . Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 2003; 17: 3029–3035.

    Article  CAS  Google Scholar 

  14. Yoo MH, Hatfield DL . The cancer stem cell theory: is it correct? Mol Cells 2008; 26: 514–516.

    CAS  Google Scholar 

  15. Gupta PB, Chaffer CL, Weinberg RA . Cancer stem cells: mirage or reality? Nat Med 2009; 15: 1010–1012.

    CAS  Google Scholar 

  16. Tomasson MH . Cancer stem cells: a guide for skeptics. J Cell Biochem 2009; 106: 745–749.

    CAS  Google Scholar 

  17. Knoepfler PS . Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. Stem Cells 2009; 27: 1050–1056.

    CAS  Google Scholar 

  18. Suva ML, Riggi N, Bernstein BE . Epigenetic reprogramming in cancer. Science 2013; 339: 1567–1570.

    CAS  Google Scholar 

  19. Ben-David U, Benvenisty N . The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer 2011; 11: 268–277.

    CAS  Google Scholar 

  20. Riggs JW, Barrilleaux BL, Varlakhanova N, Bush KM, Chan V, Knoepfler PS . Induced pluripotency and oncogenic transformation are related processes. Stem Cells Dev 2013; 22: 37–50.

    CAS  Google Scholar 

  21. Ohnishi K, Semi K, Yamamoto T, Shimizu M, Tanaka A, Mitsunaga K et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell 2014; 156: 663–677.

    CAS  Google Scholar 

  22. Spivakov M, Fisher AG . Epigenetic signatures of stem-cell identity. Nat Rev Genet 2007; 8: 263–271.

    CAS  Google Scholar 

  23. Li M, Liu GH, Izpisua Belmonte JC . Navigating the epigenetic landscape of pluripotent stem cells. Nat Rev Mol Cell Biol 2012; 13: 524–535.

    CAS  Google Scholar 

  24. Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C et al. Epigenetic stem cell signature in cancer. Nat Genet 2007; 39: 157–158.

    CAS  Google Scholar 

  25. Richly H, Aloia L, Di Croce L . Roles of the Polycomb group proteins in stem cells and cancer. Cell Death Dis 2011; 2: e204.

    CAS  Google Scholar 

  26. Fisher CL, Fisher AG . Chromatin states in pluripotent, differentiated, and reprogrammed cells. Curr Opin Genet Dev 2011; 21: 140–146.

    CAS  Google Scholar 

  27. Easwaran H, Johnstone SE, Van Neste L, Ohm J, Mosbruger T, Wang Q et al. A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Res 2012; 22: 837–849.

    CAS  Google Scholar 

  28. Sharma A, Heuck CJ, Fazzari MJ, Mehta J, Singhal S, Greally JM et al. DNA methylation alterations in multiple myeloma as a model for epigenetic changes in cancer. Wiley Interdiscip Rev Syst Biol Med 2010; 2: 654–669.

    CAS  Google Scholar 

  29. You JS, Jones PA . Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell. 2012; 22: 9–20.

    CAS  Google Scholar 

  30. Jones PA, Baylin SB . The epigenomics of cancer. Cell 2007; 128: 683–692.

    CAS  Google Scholar 

  31. Esteller M . Epigenetics in cancer. N Engl J Med 2008; 358: 1148–1159.

    CAS  Google Scholar 

  32. Patra SK, Deb M, Patra A . Molecular marks for epigenetic identification of developmental and cancer stem cells. Clin Epigenetics 2011; 2: 27–53.

    CAS  Google Scholar 

  33. Ohm JE, Mali P, Van Neste L, Berman DM, Liang L, Pandiyan K et al. Cancer-related epigenome changes associated with reprogramming to induced pluripotent stem cells. Cancer Res 2010; 70: 7662–7673.

    CAS  Google Scholar 

  34. Smith ZD, Meissner A . DNA methylation: roles in mammalian development. Nat Rev Genet 2013; 14: 204–220.

    CAS  Google Scholar 

  35. Jones PA, Liang G . Rethinking how DNA methylation patterns are maintained. Nat Rev Genet 2009; 10: 805–811.

    CAS  Google Scholar 

  36. 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 

  37. Hochedlinger K, Plath K . Epigenetic reprogramming and induced pluripotency. Development 2009; 136: 509–523.

    CAS  Google Scholar 

  38. Chen T, Ueda Y, Dodge JE, Wang Z, Li E . Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol Cell Biol 2003; 23: 5594–5605.

    CAS  Google Scholar 

  39. Tsumura A, Hayakawa T, Kumaki Y, Takebayashi S, Sakaue M, Matsuoka C et al. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells 2006; 11: 805–814.

    CAS  Google Scholar 

  40. Pawlak M, Jaenisch R . De novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells to a pluripotent state. Genes Dev 2011; 25: 1035–1040.

    CAS  Google Scholar 

  41. Baylin SB, Jones PA . A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 2011; 11: 726–734.

    CAS  Google Scholar 

  42. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363: 2424–2433.

    CAS  Google Scholar 

  43. Gao Q, Steine EJ, Barrasa MI, Hockemeyer D, Pawlak M, Fu D et al. Deletion of the de novo DNA methyltransferase Dnmt3a promotes lung tumor progression. Proc Natl Acad Sci USA 2011; 108: 18061–18066.

    CAS  Google Scholar 

  44. Robert MF, Morin S, Beaulieu N, Gauthier F, Chute IC, Barsalou A et al. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat Genet 2003; 33: 61–65.

    CAS  Google Scholar 

  45. Trowbridge JJ, Sinha AU, Zhu N, Li M, Armstrong SA, Orkin SH . Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains. Genes Dev 2012; 26: 344–349.

    CAS  Google Scholar 

  46. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009; 324: 930–935.

    CAS  Google Scholar 

  47. Wu SC, Zhang Y . Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol 2010; 11: 607–620.

    CAS  Google Scholar 

  48. Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J et al. The ground state of embryonic stem cell self-renewal. Nature 2008; 453: 519–523.

    CAS  Google Scholar 

  49. Leitch HG, McEwen KR, Turp A, Encheva V, Carroll T, Grabole N et al. Naive pluripotency is associated with global DNA hypomethylation. Nat Struct Mol Biol 2013; 20: 311–316.

    CAS  Google Scholar 

  50. Habibi E, Brinkman AB, Arand J, Kroeze LI, Kerstens HH, Matarese F et al. Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells. Cell Stem Cell 2013; 13: 360–369.

    CAS  Google Scholar 

  51. Ficz G, Hore TA, Santos F, Lee HJ, Dean W, Arand J et al. FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. Cell Stem Cell 2013; 13: 351–359.

    CAS  Google Scholar 

  52. Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J et al. Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 2011; 8: 200–213.

    CAS  Google Scholar 

  53. Gu TP, Guo F, Yang H, Wu HP, Xu GF, Liu W et al. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 2011; 477: 606–610.

    CAS  Google Scholar 

  54. Stower H . Epigenetics: Reprogramming with TET. Nat Rev Genet 2014; 15: 66.

    Google Scholar 

  55. Doege CA, Inoue K, Yamashita T, Rhee DB, Travis S, Fujita R et al. Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 2012; 488: 652–655.

    CAS  Google Scholar 

  56. Gao Y, Chen J, Li K, Wu T, Huang B, Liu W et al. Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell 2013; 12: 453–469.

    CAS  Google Scholar 

  57. Costa Y, Ding J, Theunissen TW, Faiola F, Hore TA, Shliaha PV et al. NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 2013; 495: 370–374.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  59. Feinberg AP, Vogelstein B . Hypomethylation of ras oncogenes in primary human cancers. Biochem Biophys Res Commun 1983; 111: 47–54.

    CAS  Google Scholar 

  60. Nishigaki M, Aoyagi K, Danjoh I, Fukaya M, Yanagihara K, Sakamoto H et al. Discovery of aberrant expression of R-RAS by cancer-linked DNA hypomethylation in gastric cancer using microarrays. Cancer Res. 2005; 65: 2115–2124.

    CAS  Google Scholar 

  61. Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J et al. Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 2013; 32: 663–669.

    CAS  Google Scholar 

  62. Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K et al. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 2012; 150: 1135–1146.

    CAS  Google Scholar 

  63. Yang H, Ye D, Guan KL, Xiong Y . IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res 2012; 18: 5562–5571.

    CAS  Google Scholar 

  64. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010; 17: 510–522.

    CAS  Google Scholar 

  65. Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012; 483: 479–483.

    CAS  Google Scholar 

  66. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010; 18: 553–567.

    CAS  Google Scholar 

  67. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 2011; 19: 17–30.

    CAS  Google Scholar 

  68. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 2010; 468: 839–843.

    CAS  Google Scholar 

  69. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 2011; 20: 11–24.

    CAS  Google Scholar 

  70. Song SJ, Ito K, Ala U, Kats L, Webster K, Sun SM et al. The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. Cell Stem Cell 2013; 13: 87–101.

    CAS  Google Scholar 

  71. Sun M, Song CX, Huang H, Frankenberger CA, Sankarasharma D, Gomes S et al. HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis. Proc Natl Acad Sci USA 2013; 110: 9920–9925.

    CAS  Google Scholar 

  72. Huang H, Jiang X, Li Z, Li Y, Song CX, He C et al. TET1 plays an essential oncogenic role in MLL-rearranged leukemia. Proc Natl Acad Sci USA 2013; 110: 11994–11999.

    CAS  Google Scholar 

  73. Zhang H, Zhang X, Clark E, Mulcahey M, Huang S, Shi YG . TET1 is a DNA-binding protein that modulates DNA methylation and gene transcription via hydroxylation of 5-methylcytosine. Cell Res 2010; 20: 1390–1393.

    Google Scholar 

  74. Xu C, Bian C, Lam R, Dong A, Min J . The structural basis for selective binding of non-methylated CpG islands by the CFP1 CXXC domain. Nat Commun 2011; 2: 227.

    Google Scholar 

  75. Kouzarides T . Chromatin modifications and their function. Cell 2007; 128: 693–705.

    CAS  Google Scholar 

  76. Bannister AJ, Kouzarides T . Regulation of chromatin by histone modifications. Cell Res 2011; 21: 381–395.

    CAS  Google Scholar 

  77. Cedar H, Bergman Y . Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 2009; 10: 295–304.

    CAS  Google Scholar 

  78. Zhou VW, Goren A, Bernstein BE . Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet 2011; 12: 7–18.

    Google Scholar 

  79. Esteller M . Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 2007; 8: 286–298.

    CAS  Google Scholar 

  80. van Haaften G, Dalgliesh GL, Davies H, Chen L, Bignell G, Greenman C et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet 2009; 41: 521–523.

    CAS  Google Scholar 

  81. Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 2011; 476: 298–303.

    CAS  Google Scholar 

  82. Yuen BT, Knoepfler PS . Histone H3.3 mutations: a variant path to cancer. Cancer Cell 2013; 24: 567–574.

    CAS  Google Scholar 

  83. Wu CY, Tsai YP, Wu MZ, Teng SC, Wu KJ . Epigenetic reprogramming and post-transcriptional regulation during the epithelial-mesenchymal transition. Trends Genet 2012; 28: 454–463.

    CAS  Google Scholar 

  84. Knoepfler PS . Why myc? An unexpected ingredient in the stem cell cocktail. Cell Stem Cell 2008; 2: 18–21.

    CAS  Google Scholar 

  85. Knoepfler PS, Zhang XY, Cheng PF, Gafken PR, McMahon SB, Eisenman RN . Myc influences global chromatin structure. EMBO J 2006; 25: 2723–2734.

    CAS  Google Scholar 

  86. Sauvageau M, Sauvageau G . Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell 2010; 7: 299–313.

    CAS  Google Scholar 

  87. Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M . Stem cells and cancer; the polycomb connection. Cell 2004; 118: 409–418.

    CAS  Google Scholar 

  88. Cao R, Tsukada Y, Zhang Y . Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell 2005; 20: 845–854.

    CAS  Google Scholar 

  89. Siddique HR, Saleem M . Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem Cells 2012; 30: 372–378.

    CAS  Google Scholar 

  90. Haupt Y, Bath ML, Harris AW, Adams JM . Bmi1 transgene induces lymphomas and collaborates with myc in tumorigenesis. Oncogene 1993; 8: 3161–3164.

    CAS  Google Scholar 

  91. Chiba T, Miyagi S, Saraya A, Aoki R, Seki A, Morita Y et al. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res 2008; 68: 7742–7749.

    CAS  Google Scholar 

  92. Yoshikawa R, Tsujimura T, Tao L, Kamikonya N, Fujiwara Y . The oncoprotein and stem cell renewal factor BMI1 associates with poor clinical outcome in oesophageal cancer patients undergoing preoperative chemoradiotherapy. BMC Cancer 2012; 12: 461.

    CAS  Google Scholar 

  93. Abdouh M, Facchino S, Chatoo W, Balasingam V, Ferreira J, Bernier G . BMI1 sustains human glioblastoma multiforme stem cell renewal. J Neurosci 2009; 29: 8884–8896.

    CAS  Google Scholar 

  94. Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M . Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 1999; 13: 2678–2690.

    CAS  Google Scholar 

  95. Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH et al. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol 2010; 12: 982–992.

    Google Scholar 

  96. Raimondi C, Gianni W, Cortesi E, Gazzaniga P . Cancer stem cells and epithelial-mesenchymal transition: revisiting minimal residual disease. Curr Cancer Drug Targets 2010; 10: 496–508.

    CAS  Google Scholar 

  97. Cao L, Bombard J, Cintron K, Sheedy J, Weetall ML, Davis TW . BMI1 as a novel target for drug discovery in cancer. J Cell Biochem 2011; 112: 2729–2741.

    CAS  Google Scholar 

  98. Song SJ, Poliseno L, Song MS, Ala U, Webster K, Ng C et al. MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 2013; 154: 311–324.

    CAS  Google Scholar 

  99. Dalerba P, Clarke MF . Oncogenic miRNAs and the perils of losing control of a stem cell's epigenetic identity. Cell Stem Cell 2013; 13: 5–6.

    CAS  Google Scholar 

  100. van der Lugt NM, Domen J, Linders K, van Roon M, Robanus-Maandag E, te Riele H et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev 1994; 8: 757–769.

    CAS  Google Scholar 

  101. Ding X, Lin Q, Ensenat-Waser R, Rose-John S, Zenke M . Polycomb group protein Bmi1 promotes hematopoietic cell development from embryonic stem cells. Stem Cells Dev 2012; 21: 121–132.

    CAS  Google Scholar 

  102. Onder TT, Kara N, Cherry A, Sinha AU, Zhu N, Bernt KM et al. Chromatin-modifying enzymes as modulators of reprogramming. Nature 2012; 483: 598–602.

    CAS  Google Scholar 

  103. Moon JH, Heo JS, Kim JS, Jun EK, Lee JH, Kim A et al. Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1. Cell Res 2011; 21: 1305–1315.

    CAS  Google Scholar 

  104. Sparmann A, van Lohuizen M . Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 2006; 6: 846–856.

    CAS  Google Scholar 

  105. Kondo Y, Shen L, Cheng AS, Ahmed S, Boumber Y, Charo C et al. Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet 2008; 40: 741–750.

    CAS  Google Scholar 

  106. Khan SN, Jankowska AM, Mahfouz R, Dunbar AJ, Sugimoto Y, Hosono N et al. Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies. Leukemia 2013; 27: 1301–1309.

    CAS  Google Scholar 

  107. Thiel AT, Feng Z, Pant DK, Chodosh LA, Hua X . The trithorax protein partner menin acts in tandem with EZH2 to suppress C/EBPalpha and differentiation in MLL-AF9 leukemia. Haematologica 2013; 98: 918–927.

    CAS  Google Scholar 

  108. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002; 419: 624–629.

    CAS  Google Scholar 

  109. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA 2003; 100: 11606–11611.

    CAS  Google Scholar 

  110. Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH et al. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell 2011; 19: 86–100.

    CAS  Google Scholar 

  111. Bao B, Ali S, Banerjee S, Wang Z, Logna F, Azmi AS et al. Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res 2012; 72: 335–345.

    CAS  Google Scholar 

  112. Crea F . EZH2 and cancer stem cells: fact or fiction? Epigenomics 2011; 3: 127–128.

    CAS  Google Scholar 

  113. Crea F, Fornaro L, Paolicchi E, Masi G, Frumento P, Loupakis F et al. An EZH2 polymorphism is associated with clinical outcome in metastatic colorectal cancer patients. Ann Oncol 2012; 23: 1207–1213.

    CAS  Google Scholar 

  114. Suva ML, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle JC et al. EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res 2009; 69: 9211–9218.

    CAS  Google Scholar 

  115. Wang J, Wang H, Li Z, Wu Q, Lathia JD, McLendon RE et al. c-Myc is required for maintenance of glioma cancer stem cells. PLoS ONE 2008; 3: e3769.

    Google Scholar 

  116. Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006; 439: 871–874.

    CAS  Google Scholar 

  117. Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 2006; 441: 349–353.

    CAS  Google Scholar 

  118. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 2006; 125: 301–313.

    CAS  Google Scholar 

  119. Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X et al. EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell 2008; 32: 491–502.

    CAS  Google Scholar 

  120. Pereira CF, Piccolo FM, Tsubouchi T, Sauer S, Ryan NK, Bruno L et al. ESCs require PRC2 to direct the successful reprogramming of differentiated cells toward pluripotency. Cell Stem Cell 2010; 6: 547–556.

    CAS  Google Scholar 

  121. Neri F, Zippo A, Krepelova A, Cherubini A, Rocchigiani M, Oliviero S . Myc regulates the transcription of the PRC2 gene to control the expression of developmental genes in embryonic stem cells. Mol Cell Biol 2012; 32: 840–851.

    CAS  Google Scholar 

  122. Ding X, Wang X, Sontag S, Qin J, Wanek P, Lin Q et al. The polycomb protein Ezh2 impacts on induced pluripotent stem cell generation. Stem Cells Dev 2014; 23: 931–940.

    CAS  Google Scholar 

  123. Grimaud C, Negre N, Cavalli G . From genetics to epigenetics: the tale of Polycomb group and trithorax group genes. Chromosome Res 2006; 14: 363–375.

    CAS  Google Scholar 

  124. Schuettengruber B, Martinez AM, Iovino N, Cavalli G . Trithorax group proteins: switching genes on and keeping them active. Nat Rev Mol Cell Biol 2011; 12: 799–814.

    CAS  Google Scholar 

  125. Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell 2002; 10: 1107–1117.

    CAS  Google Scholar 

  126. Krivtsov AV, Armstrong SA . MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 2007; 7: 823–833.

    CAS  Google Scholar 

  127. Milne TA, Kim J, Wang GG, Stadler SC, Basrur V, Whitcomb SJ et al. Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis. Mol Cell 2010; 38: 853–863.

    CAS  Google Scholar 

  128. Smith LL, Yeung J, Zeisig BB, Popov N, Huijbers I, Barnes J et al. Functional crosstalk between Bmi1 and MLL/Hoxa9 axis in establishment of normal hematopoietic and leukemic stem cells. Cell Stem Cell 2011; 8: 649–662.

    CAS  Google Scholar 

  129. Ansari KI, Kasiri S, Mandal SS . Histone methylase MLL1 has critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo. Oncogene 2013; 32: 3359–3370.

    CAS  Google Scholar 

  130. Heddleston JM, Wu Q, Rivera M, Minhas S, Lathia JD, Sloan AE et al. Hypoxia-induced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential. Cell Death Differ 2012; 19: 428–439.

    CAS  Google Scholar 

  131. Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 2009; 15: 501–513.

    CAS  Google Scholar 

  132. Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol 2006; 13: 713–719.

    CAS  Google Scholar 

  133. Ang YS, Tsai SY, Lee DF, Monk J, Su J, Ratnakumar K et al. Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell 2011; 145: 183–197.

    CAS  Google Scholar 

  134. Orkin SH, Hochedlinger K . Chromatin connections to pluripotency and cellular reprogramming. Cell 2011; 145: 835–850.

    CAS  Google Scholar 

  135. Jiang H, Shukla A, Wang X, Chen WY, Bernstein BE, Roeder RG . Role for Dpy-30 in ES cell-fate specification by regulation of H3K4 methylation within bivalent domains. Cell 2011; 144: 513–525.

    CAS  Google Scholar 

  136. Amente S, Lania L, Majello B . The histone LSD1 demethylase in stemness and cancer transcription programs. Biochim Biophys Acta 2013; 1829: 981–986.

    CAS  Google Scholar 

  137. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004; 119: 941–953.

    CAS  Google Scholar 

  138. Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 2005; 437: 436–439.

    CAS  Google Scholar 

  139. Schulte JH, Lim S, Schramm A, Friedrichs N, Koster J, Versteeg R et al. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res 2009; 69: 2065–2071.

    CAS  Google Scholar 

  140. Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R et al. Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res 2006; 66: 11341–11347.

    CAS  Google Scholar 

  141. Lim S, Janzer A, Becker A, Zimmer A, Schule R, Buettner R et al. Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis 2010; 31: 512–520.

    CAS  Google Scholar 

  142. Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 2012; 21: 473–487.

    CAS  Google Scholar 

  143. Wang J, Lu F, Ren Q, Sun H, Xu Z, Lan R et al. Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res 2011; 71: 7238–7249.

    CAS  Google Scholar 

  144. Wang J, Scully K, Zhu X, Cai L, Zhang J, Prefontaine GG et al. Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 2007; 446: 882–887.

    CAS  Google Scholar 

  145. Wang J, Hevi S, Kurash JK, Lei H, Gay F, Bajko J et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet 2009; 41: 125–129.

    CAS  Google Scholar 

  146. Whyte WA, Bilodeau S, Orlando DA, Hoke HA, Frampton GM, Foster CT et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 2012; 482: 221–225.

    CAS  Google Scholar 

  147. Yang P, Wang Y, Chen J, Li H, Kang L, Zhang Y et al. RCOR2 is a subunit of the LSD1 complex that regulates ESC property and substitutes for SOX2 in reprogramming somatic cells to pluripotency. Stem Cells 2011; 29: 791–801.

    CAS  Google Scholar 

  148. Hochedlinger K, Yamada Y, Beard C, Jaenisch R . Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 2005; 121: 465–477.

    CAS  Google Scholar 

  149. Korkaya H, Wicha MS . HER2 and breast cancer stem cells: more than meets the eye. Cancer Res 2013; 73: 3489–3493.

    CAS  Google Scholar 

  150. Chen K, Huang YH, Chen JL . Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin 2013; 34: 732–740.

    CAS  Google Scholar 

  151. Liu L, Andrews LG, Tollefsbol TO . Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death. Oncogene 2006; 25: 4370–4375.

    CAS  Google Scholar 

  152. Facchino S, Abdouh M, Bernier G . Brain cancer stem cells: current status on glioblastoma multiforme. Cancers (Basel) 2011; 3: 1777–1797.

    CAS  Google Scholar 

  153. Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T et al. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med 2014; 20: 29–36.

    CAS  Google Scholar 

  154. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 2012; 8: 890–896.

    CAS  Google Scholar 

  155. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012; 492: 108–112.

    CAS  Google Scholar 

  156. Kim W, Bird GH, Neff T, Guo G, Kerenyi MA, Walensky LD et al. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat Chem Biol 2013; 9: 643–650.

    CAS  Google Scholar 

  157. Mack GS . Epigenetic cancer therapy makes headway. J Natl Cancer Inst 2006; 98: 1443–1444.

    Google Scholar 

  158. de la Serna IL, Ohkawa Y, Imbalzano AN . Chromatin remodelling in mammalian differentiation: lessons from ATP-dependent remodellers. Nat Rev Genet 2006; 7: 461–473.

    CAS  Google Scholar 

  159. Roberts CW, Orkin SH . The SWI/SNF complex—chromatin and cancer. Nat Rev Cancer 2004; 4: 133–142.

    CAS  Google Scholar 

  160. Reisman D, Glaros S, Thompson EA . The SWI/SNF complex and cancer. Oncogene 2009; 28: 1653–1668.

    CAS  Google Scholar 

  161. Ho L, Ronan JL, Wu J, Staahl BT, Chen L, Kuo A et al. An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Proc Natl Acad Sci USA 2009; 106: 5181–5186.

    CAS  Google Scholar 

  162. Krasteva V, Buscarlet M, Diaz-Tellez A, Bernard MA, Crabtree GR, Lessard JA . The BAF53a subunit of SWI/SNF-like BAF complexes is essential for hemopoietic stem cell function. Blood 2012; 120: 4720–4732.

    CAS  Google Scholar 

  163. Singhal N, Graumann J, Wu G, Arauzo-Bravo MJ, Han DW, Greber B et al. Chromatin-remodeling components of the BAF complex facilitate reprogramming. Cell 2010; 141: 943–955.

    CAS  Google Scholar 

Download references

Acknowledgements

We thank Bonnie Barrilleaux and Benjamin Yuen for providing feedback on this manuscript. This work was supported by an NIH Grant 1R01GM100782 and a CIRM Grant RN2-00922-1 (both to PSK).

Author information

Authors and Affiliations

  1. Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine, Davis, CA, USA,

    P-Y Tung & P S Knoepfler

  2. UC Davis Genome Center, University of California Davis, Davis, CA, USA

    P-Y Tung & P S Knoepfler

  3. UC Davis Comprehensive Cancer Center, Sacramento, CA, USA,

    P-Y Tung & P S Knoepfler

  4. Institute of Pediatric Regenerative Medicine, Shriners Hospital For Children Northern California, Sacramento, CA, USA

    P-Y Tung & P S Knoepfler

Authors
  1. P-Y Tung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P S Knoepfler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P S Knoepfler.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tung, PY., Knoepfler, P. Epigenetic mechanisms of tumorigenicity manifesting in stem cells. Oncogene 34, 2288–2296 (2015). https://doi.org/10.1038/onc.2014.172

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.172

  • Springer Nature Limited

This article is cited by

Search

Navigation