iPS Cell Technology for Dissecting Cancer Epigenetics

  • Hirofumi Shibata
  • Yasuhiro YamadaEmail author
Part of the Current Human Cell Research and Applications book series (CHCRA)


A dynamic reorganization of epigenetic regulation takes place during cellular reprogramming. Given that reprogramming does not require changes in the underlying genome information, reprogramming technology can be used to actively modify the epigenetic regulation and thus is useful for studying the genome-epigenome relationship. Cancer cells harbor both genetic and epigenetic alterations. Although the causal role of genetic aberrations on cancer development has been well characterized by reverse genetics in vivo, the impact of epigenetic abnormalities remains to be fully understood, especially in vivo. Recent genome-wide sequencing studies have identified frequent mutations at epigenetic modifier genes, thus indicating that epigenetic alterations in cancer could be the consequence of genetic mutations. However, recent studies that utilized reprogramming technology for cancer research have demonstrated cellular context-associated epigenetic regulation that is independent of genetic mutations and plays a critical role on both the development and maintenance of cancer cells. In this review, we propose that reprogramming technology could be a powerful tool for dissecting the role of epigenetic regulation in cancer biology.


Cancer Reprogramming technology Epigenetics DNA methylation In vivo reprogramming 



Acute myeloid leukemia


Differentially methylated regions


Embryonic stem cells




Induced pluripotent cancer cells


Induced pluripotent stem cells


Loss of heterogeneity


Nuclear transferred embryonic stem cells


Pancreatic ductal adenocarcinoma


Polycomb repressive complex 2


Reactive oxygen species


Reprogrammed tumor cells




Somatic cell nuclear transfer


Tumor-propagating cells


  1. 1.
    Fearon ER, Hamilton SR, Vogelstein B. Clonal analysis of human colorectal tumors. Science (New York, NY). 1987;238:193–7.CrossRefGoogle Scholar
  2. 2.
    Nowell PC. The clonal evolution of tumor cell populations. Science (New York, NY). 1976;194:23–8.CrossRefGoogle Scholar
  3. 3.
    Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3:415–28. Scholar
  4. 4.
    Hattori N, Ushijima T. Compendium of aberrant DNA methylation and histone modifications in cancer. Biochem Biophys Res Commun. 2014;455:3–9. Scholar
  5. 5.
    Kondo Y, Katsushima K, Ohka F, Natsume A, Shinjo K. Epigenetic dysregulation in glioma. Cancer Sci. 2014;105:363–9.CrossRefGoogle Scholar
  6. 6.
    Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983;301:89–92.CrossRefGoogle Scholar
  7. 7.
    Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R. DNA hypomethylation leads to elevated mutation rates. Nature. 1998;395:89–93. Scholar
  8. 8.
    Gaudet F, et al. Induction of tumors in mice by genomic hypomethylation. Science (New York, NY). 2003;300:489–92. Scholar
  9. 9.
    Eden A, Gaudet F, Waghmare A, Jaenisch R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science (New York, NY). 2003;300:455. Scholar
  10. 10.
    Laird PW, et al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell. 1995;81:197–205.CrossRefGoogle Scholar
  11. 11.
    Yamada Y, et al. Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc Natl Acad Sci U S A. 2005;102:13580–5. Scholar
  12. 12.
    Hatano Y, et al. Reducing DNA methylation suppresses colon carcinogenesis by inducing tumor cell differentiation. Carcinogenesis. 2015;36:719–29. Scholar
  13. 13.
    Lin H, et al. Suppression of intestinal neoplasia by deletion of Dnmt3b. Mol Cell Biol. 2006;26:2976–83. Scholar
  14. 14.
    Linhart HG, et al. Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev. 2007;21:3110–22. Scholar
  15. 15.
    Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–54. Scholar
  16. 16.
    Belinsky SA, et al. Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci U S A. 1998;95:11891–6.CrossRefGoogle Scholar
  17. 17.
    Das PM, Singal R. DNA methylation and cancer. J Clin Oncol. 2004;22:4632–42. Scholar
  18. 18.
    Esteller M, et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 2000;92:564–9.CrossRefGoogle Scholar
  19. 19.
    Rainier S, et al. Relaxation of imprinted genes in human cancer. Nature. 1993;362:747–9. Scholar
  20. 20.
    Ogawa O, et al. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms’ tumour. Nature. 1993;362:749–51. Scholar
  21. 21.
    Bjornsson HT, et al. Epigenetic specificity of loss of imprinting of the IGF2 gene in Wilms tumors. J Natl Cancer Inst. 2007;99:1270–3. Scholar
  22. 22.
    DeBaun MR, et al. Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects. Am J Hum Genet. 2002;70:604–11. Scholar
  23. 23.
    Ley TJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424–33. Scholar
  24. 24.
    Schwartzentruber J, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482:226–31. Scholar
  25. 25.
    Versteege I, et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. 1998;394:203–6. Scholar
  26. 26.
    Biegel JA, et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 1999;59:74–9.PubMedGoogle Scholar
  27. 27.
    Jones S, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science (New York, NY). 2010;330:228–31. Scholar
  28. 28.
    Wiegand KC, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010;363:1532–43. Scholar
  29. 29.
    Couronne L, Bastard C, Bernard OA. TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med. 2012;366:95–6. Scholar
  30. 30.
    Ribeiro AF, et al. Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. Blood. 2012;119:5824–31. Scholar
  31. 31.
    Delhommeau F, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–301. Scholar
  32. 32.
    McCabe MT, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492:108–12. Scholar
  33. 33.
    Morin RD, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42:181–5. Scholar
  34. 34.
    Ernst T, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42:722–6. Scholar
  35. 35.
    McKay JA, Waltham KJ, Williams EA, Mathers JC. Folate depletion during pregnancy and lactation reduces genomic DNA methylation in murine adult offspring. Genes Nutr. 2011;6:189–96. Scholar
  36. 36.
    Sie KK, et al. Effect of maternal and postweaning folic acid supplementation on colorectal cancer risk in the offspring. Gut. 2011;60:1687–94. Scholar
  37. 37.
    Wilson VL, Jones PA. DNA methylation decreases in aging but not in immortal cells. Science (New York, NY). 1983;220:1055–7.CrossRefGoogle Scholar
  38. 38.
    Wilson VL, Smith RA, Ma S, Cutler RG. Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem. 1987;262:9948–51.PubMedGoogle Scholar
  39. 39.
    Talens RP, et al. Epigenetic variation during the adult lifespan: cross-sectional and longitudinal data on monozygotic twin pairs. Aging Cell. 2012;11:694–703. Scholar
  40. 40.
    Issa JP, Vertino PM, Boehm CD, Newsham IF, Baylin SB. Switch from monoallelic to biallelic human IGF2 promoter methylation during aging and carcinogenesis. Proc Natl Acad Sci U S A. 1996;93:11757–62.CrossRefGoogle Scholar
  41. 41.
    Sakatani T, et al. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science (New York, NY). 2005;307:1976–8. Scholar
  42. 42.
    Issa JP. Aging and epigenetic drift: a vicious cycle. J Clin Invest. 2014;124:24–9. Scholar
  43. 43.
    Maekita T, et al. High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res. 2006;12:989–95. Scholar
  44. 44.
    Schulmann K, et al. Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett’s-associated neoplastic progression and predicts progression risk. Oncogene. 2005;24:4138–48. Scholar
  45. 45.
    Moss SF, Blaser MJ. Mechanisms of disease: inflammation and the origins of cancer. Nat Clin Pract Oncol. 2005;2:90–7. quiz 91 p following 113.CrossRefPubMedGoogle Scholar
  46. 46.
    Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012;13:97–109. Scholar
  47. 47.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76. Scholar
  48. 48.
    Takahashi K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72. Scholar
  49. 49.
    Polo JM, et al. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell. 2012;151:1617–32. Scholar
  50. 50.
    Chronis C, et al. Cooperative binding of transcription factors orchestrates reprogramming. Cell. 2017;168:442–459.e420. Scholar
  51. 51.
    Ben-Porath I, et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 2008;40:499–507. Scholar
  52. 52.
    Gidekel S, Pizov G, Bergman Y, Pikarsky E. Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell. 2003;4:361–70.CrossRefGoogle Scholar
  53. 53.
    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;121:465–77. Scholar
  54. 54.
    Lu X, Mazur SJ, Lin T, Appella E, Xu Y. The pluripotency factor nanog promotes breast cancer tumorigenesis and metastasis. Oncogene. 2014;33:2655–64. Scholar
  55. 55.
    Boumahdi S, et al. SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature. 2014;511:246–50. Scholar
  56. 56.
    Blelloch RH, et al. Nuclear cloning of embryonal carcinoma cells. Proc Natl Acad Sci U S A. 2004;101:13985–90. Scholar
  57. 57.
    Hochedlinger K, et al. Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev. 2004;18:1875–85. Scholar
  58. 58.
    Fodde R. The APC gene in colorectal cancer. Eur J Cancer. 2002;38:867–71.CrossRefGoogle Scholar
  59. 59.
    Sanz MA, Martin G, Diaz-Mediavilla J. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1998;338:393–4. Scholar
  60. 60.
    Carette JE, et al. Generation of iPSCs from cultured human malignant cells. Blood. 2010;115:4039–42. Scholar
  61. 61.
    Bernhardt M, et al. Melanoma-derived iPCCs show differential tumorigenicity and therapy response. Stem Cell Rep. 2017;8:1379–91. Scholar
  62. 62.
    Hashimoto K, et al. Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior. Proc Natl Acad Sci U S A. 2017;114:758–63. Scholar
  63. 63.
    Kim J, et al. An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. Cell Rep. 2013;3:2088–99. Scholar
  64. 64.
    Suva ML, et al. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell. 2014;157:580–94. Scholar
  65. 65.
    Shaffer SM, et al. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature. 2017;546:431–5. Scholar
  66. 66.
    Stadtfeld M, Maherali N, Borkent M, Hochedlinger K. A reprogrammable mouse strain from gene-targeted embryonic stem cells. Nat Methods. 2010;7:53–5. Scholar
  67. 67.
    Abad M, et al. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature. 2013;502:340–5. Scholar
  68. 68.
    Ohnishi K, et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell. 2014;156:663–77. Scholar
  69. 69.
    Ruteshouser EC, Robinson SM, Huff V. Wilms tumor genetics: mutations in WT1, WTX, and CTNNB1 account for only about one-third of tumors. Genes Chromosomes Cancer. 2008;47:461–70. Scholar
  70. 70.
    Hong H, et al. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature. 2009;460:1132–5. Scholar
  71. 71.
    Li H, et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature. 2009;460:1136–9. Scholar
  72. 72.
    Liu XS, et al. Editing DNA methylation in the mammalian genome. Cell. 2016;167:233–247.e217. Scholar
  73. 73.
    Morita S, et al. Targeted DNA demethylation in vivo using dCas9-peptide repeat and scFv-TET1 catalytic domain fusions. Nat Biotechnol. 2016;34:1060–5. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA)Kyoto UniversityKyotoJapan
  2. 2.Department of Otolaryngology, Gifu University Graduate School of MedicineGifu UniversityGifuJapan
  3. 3.Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical ScienceUniversity of TokyoTokyoJapan

Personalised recommendations