Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting the cancer epigenome for therapy

Key Points

  • Tumour cells often have mutations in genes that encode regulators of the epigenome.

  • Cancers use both genetic and epigenetic alterations to evolve and develop resistance to immune surveillance and chemotherapy.

  • DNA methylation inhibitors are the standard of care for certain haematological malignancies and form the backbones of many trials in solid tumours.

  • Several new drugs that target histone modifications are being tested in clinical trials.

  • DNA methylation inhibitors activate not only abnormally silenced genes, but also cancer testis antigens (CTAs) and endogenous retroviruses (ERVs). Activation of CTAs and ERVs may increase the visibility of the tumour to the immune system and increase the efficacy of immunotherapy.

  • Therapies that combine epigenetic drugs and standard chemotherapy will become important clinical tools in the future.

Abstract

Next-generation sequencing has revealed that more than 50% of human cancers harbour mutations in enzymes that are involved in chromatin organization. Tumour cells not only are activated by genetic and epigenetic alterations, but also routinely use epigenetic processes to ensure their escape from chemotherapy and host immune surveillance. Hence, a growing emphasis of recent drug discovery efforts has been on targeting the epigenome, including DNA methylation and histone modifications, with several new drugs being tested and some already approved by the US Food and Drug Administration (FDA). The future will see the increasing success of combining epigenetic drugs with other therapies. As epigenetic drugs target the epigenome as a whole, these true 'genomic medicines' lessen the need for precision approaches to individualized therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Modulation of covalent modifications on chromatin.
Figure 2: Somatic inheritance of acquired traits in cancer.
Figure 3: Targeting chromatin for therapy.
Figure 4: Activation of constitutively and de novo methylated elements by DNMT inhibitors.

Similar content being viewed by others

References

  1. Tessarz, P. & Kouzarides, T. Histone core modifications regulating nucleosome structure and dynamics. Nat. Rev. Mol. Cell Biol. 15, 703–708 (2014).

    CAS  PubMed  Google Scholar 

  2. Roadmap Epigenomics Consortium et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).

  3. Beck, S. et al. A blueprint for an international cancer epigenome consortium. A report from the AACR Cancer Epigenome Task Force. Cancer Res. 72, 6319–6324 (2012).

    CAS  PubMed  Google Scholar 

  4. Cancer Genome Atlas Research Network et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 45, 1113–1120 (2013).

  5. Kretzmer, H. et al. DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control. Nat. Genet. 47, 1316–1325 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. You, J. S. & Jones, P. A. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 22, 9–20 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Biegel, J. A., Busse, T. M. & Weissman, B. E. SWI/SNF chromatin remodeling complexes and cancer. Am. J. Med. Genet. C. Semin. Med. Genet. 166C, 350–366 (2014).

    PubMed  Google Scholar 

  8. Mack, S. C. et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506, 445–450 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kadoch, C. & Crabtree, G. R. Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci. Adv. 1, e1500447 (2015). This is an excellent review of chromatin-remodelling complexes.

    PubMed  PubMed Central  Google Scholar 

  10. Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016).

    CAS  PubMed  Google Scholar 

  14. Yamazaki, J. et al. TET2 mutations affect non-CpG island DNA methylation at enhancers and transcription factor binding sites in chronic myelomonocytic leukemia. Cancer Res. 75, 2833–2843 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Russler-Germain, D. A. et al. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell 25, 442–454 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lu, C. et al. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 352, 844–849 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bender, S. et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24, 660–672 (2013).

    CAS  PubMed  Google Scholar 

  18. Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33, 245–254 (2003).

    CAS  PubMed  Google Scholar 

  19. Kaufman, C. K. et al. A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation. Science 351, aad2197 (2016). A breakthrough paper demonstrating the importance of epigenetic states on the expression of oncogenic phenotype.

    PubMed  PubMed Central  Google Scholar 

  20. Johann, P. D. et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29, 379–393 (2016).

    CAS  PubMed  Google Scholar 

  21. Oakes, C. C. et al. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat. Genet. 48, 253–264 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Pfeifer, G. P. Environmental exposures and mutational patterns of cancer genomes. Genome Med. 2, 54 (2010).

    PubMed  PubMed Central  Google Scholar 

  23. Rideout, W. M. 3rd, Coetzee, G. A., Olumi, A. F. & Jones, P. A. 5-methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 249, 1288–1290 (1990).

    CAS  PubMed  Google Scholar 

  24. Bollati, V. et al. Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res. 67, 876–880 (2007).

    CAS  PubMed  Google Scholar 

  25. Issa, J. P. et al. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat. Genet. 7, 536–540 (1994).

    CAS  PubMed  Google Scholar 

  26. Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013); erratum 16, 96 (2015).

    PubMed  PubMed Central  Google Scholar 

  27. Blaschke, K. et al. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 500, 222–226 (2013). A key paper emphasizing the important role of vitamin C as a cofactor for the TET enzymes.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Delhommeau, F. et al. Mutation in TET2 in myeloid cancers. N. Engl. J. Med. 360, 2289–2301 (2009).

    PubMed  Google Scholar 

  29. Polo, S. E., Kaidi, A., Baskcomb, L., Galanty, Y. & Jackson, S. P. Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4. EMBO J. 29, 3130–3139 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Smeenk, G. et al. The NuRD chromatin-remodeling complex regulates signaling and repair of DNA damage. J. Cell Biol. 190, 741–749 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Chou, D. M. et al. A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage. Proc. Natl Acad. Sci. USA 107, 18475–18480 (2010).

    CAS  PubMed  Google Scholar 

  32. O'Hagan, H. M., Mohammad, H. P. & Baylin, S. B. Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genet. 4, e1000155 (2008).

    PubMed  PubMed Central  Google Scholar 

  33. O'Hagan, H. M. et al. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and Polycomb members to promoter CpG Islands. Cancer Cell 20, 606–619 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Bhadury, J. et al. BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma. Proc. Natl Acad. Sci. USA 111, E2721–E2730 (2014).

    CAS  PubMed  Google Scholar 

  35. Yang, X. et al. Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 26, 577–590 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Jones, P. A. & Taylor, S. M. Cellular differentiation, cytidine analogs and DNA methylation. Cell 20, 85–93 (1980).

    CAS  PubMed  Google Scholar 

  37. Issa, J. P. et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 103, 1635–1640 (2004).

    CAS  PubMed  Google Scholar 

  38. Fenaux, P. et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 10, 223–232 (2009). A key paper demonstrating the efficacy of DNMTi in the treatment of MDS.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Lubbert, M. et al. Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group. Ann. Hematol. 95, 191–199 (2016).

    PubMed  Google Scholar 

  40. Oki, Y., Jelinek, J., Shen, L., Kantarjian, H. M. & Issa, J. P. Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia. Blood 111, 2382–2384 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Tsai, H. C. et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21, 430–446 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Qin, T. et al. Mechanisms of resistance to decitabine in the myelodysplastic syndrome. PLoS ONE 6, e23372 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Prébet, T. et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J. Clin. Oncol. 29, 3322–3327 (2011).

    PubMed  PubMed Central  Google Scholar 

  44. Stewart, D. J. et al. Decitabine effect on tumor global DNA methylation and other parameters in a phase I trial in refractory solid tumors and lymphomas. Clin. Cancer Res. 15, 3881–3888 (2009).

    CAS  PubMed  Google Scholar 

  45. Issa, J. P. et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 16, 1099–1110 (2015). This paper helped in the development of guadecitabine, the first new DNMT inhibitor in four decades.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Richon, V. M. et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc. Natl Acad. Sci. USA 95, 3003–3007 (1998).

    CAS  PubMed  Google Scholar 

  47. Falkenberg, K. J. & Johnstone, R. W. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discov. 13, 673–691 (2014).

    CAS  PubMed  Google Scholar 

  48. San-Miguel, J. F. et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 15, 1195–1206 (2014).

    CAS  PubMed  Google Scholar 

  49. Batty, N., Malouf, G. G. & Issa, J. P. Histone deacetylase inhibitors as anti-neoplastic agents. Cancer Lett. 280, 192–200 (2009).

    CAS  PubMed  Google Scholar 

  50. Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Lovén, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).

    PubMed  PubMed Central  Google Scholar 

  53. Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42, 181–185 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. McCabe, M. T. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108–112 (2012).

    CAS  PubMed  Google Scholar 

  55. Stein, E. M. IDH2 inhibition in AML: finally progress? Best Pract. Res. Clin. Haematol. 28, 112–115 (2015).

    PubMed  Google Scholar 

  56. Tateishi, K. et al. Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion. Cancer Cell 28, 773–784 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626–630 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Raynal, N. J. et al. DNA methylation does not stably lock gene expression but instead serves as a molecular mark for gene silencing memory. Cancer Res. 72, 1170–1181 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Turcan, S. et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT inhibitor decitabine. Oncotarget 4, 1729–1736 (2013).

    PubMed  PubMed Central  Google Scholar 

  60. Daigle, S. R. et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53–65 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Mohammad, H. P. et al. A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC. Cancer Cell 28, 57–69 (2015).

    CAS  PubMed  Google Scholar 

  62. Shankar, S. R. et al. G9a, a multipotent regulator of gene expression. Epigenetics 8, 16–22 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Ntziachristos, P. et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514, 513–517 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Raynal, N. J. et al. Targeting calcium signaling induces epigenetic reactivation of tumor suppressor genes in cancer. Cancer Res. 76, 1494–1505 (2016).

    CAS  PubMed  Google Scholar 

  65. Qin, T. et al. Effect of cytarabine and decitabine in combination in human leukemic cell lines. Clin. Cancer Res. 13, 4225–4232 (2007).

    CAS  PubMed  Google Scholar 

  66. Yang, A. S. et al. DNA methylation changes after 5-aza-2′-deoxycytidine therapy in patients with leukemia. Cancer Res. 66, 5495–5503 (2006).

    CAS  PubMed  Google Scholar 

  67. Kantarjian, H. et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109, 52–57 (2007).

    CAS  PubMed  Google Scholar 

  68. Daskalakis, M. et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment. Blood 100, 2957–2964 (2002). This paper definitively showed the demethylation of a tumour suppressor gene in patients.

    CAS  PubMed  Google Scholar 

  69. Aparicio, A. et al. LINE-1 methylation in plasma DNA as a biomarker of activity of DNA methylation inhibitors in patients with solid tumors. Epigenetics 4, 176–184 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Prebet, T. et al. Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study. Br. J. Haematol. 172, 384–391 (2015).

    PubMed  PubMed Central  Google Scholar 

  71. Shen, L. et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J. Clin. Oncol. 28, 605–613 (2010).

    CAS  PubMed  Google Scholar 

  72. Fandy, T. E. et al. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood 114, 2764–2773 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Wijermans, P. et al. Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J. Clin. Oncol. 18, 956–962 (2000).

    CAS  PubMed  Google Scholar 

  74. Issa, J. P. & Kantarjian, H. M. Targeting DNA methylation. Clin. Cancer Res. 15, 3938–3946 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

  76. Bejar, R. et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 124, 2705–2712 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Itzykson, R. et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia 25, 1147–1152 (2011).

    CAS  PubMed  Google Scholar 

  78. Traina, F. et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia 28, 78–87 (2014).

    CAS  PubMed  Google Scholar 

  79. Bender, C. M., Pao, M. M. & Jones, P. A. Inhibition of DNA methylation by 5-aza-2′-deoxycytidine suppresses the growth of human tumor cell lines. Cancer Res. 58, 95–101 (1998).

    CAS  PubMed  Google Scholar 

  80. McGarvey, K. M. et al. Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state. Cancer Res. 66, 3541–3549 (2006).

    CAS  PubMed  Google Scholar 

  81. Lin, J. C. et al. Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island. Cancer Cell 12, 432–444 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Saito, Y. et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 9, 435–443 (2006).

    CAS  PubMed  Google Scholar 

  83. Baylin, S. B. in Stem Book (ed. Girard, L.) (Harvard Stem Cell Insitute, 2009).

    Google Scholar 

  84. Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome — biological and translational implications. Nat. Rev. Cancer 11, 726–734 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Janzen, V. et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421–426 (2006).

    CAS  PubMed  Google Scholar 

  86. Akala, O. O. et al. Long-term haematopoietic reconstitution by Trp53−/− p16 Ink4a−/− p19Arf−/− multipotent progenitors. Nature 453, 228–232 (2008).

    CAS  PubMed  Google Scholar 

  87. Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683–692 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010). A key paper demonstrating the importance of epigenetic mechanisms in drug resistance.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Weber, J. et al. Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2′-deoxycytidine. Cancer Res. 54, 1766–1771 (1994).

    CAS  PubMed  Google Scholar 

  90. Karpf, A. R. & Jones, D. A. Reactivating the expression of methylation silenced genes in human cancer. Oncogene 21, 5496–5503 (2002).

    CAS  PubMed  Google Scholar 

  91. Karpf, A. R. et al. Inhibition of DNA methyltransferase stimulates the expression of signal transducer and activator of transcription 1, 2, and 3 genes in colon tumor cells. Proc. Natl Acad. Sci. USA 96, 14007–14012 (1999).

    CAS  PubMed  Google Scholar 

  92. Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Roulois, D. et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 961–973 (2015). References 92 and 93 were the first to link activation of ERVs to cellular response.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Constantinides, P. G., Taylor, S. M. & Jones, P. A. Phenotypic conversion of cultured mouse embryo cells by aza pyrimidine nucleosides. Dev. Biol. 66, 57–71 (1978).

    CAS  PubMed  Google Scholar 

  95. DeVita, V. T. & DeVita-Raeburn, E. The Death of Cancer (Sarah Crighton Books, 2015).

    Google Scholar 

  96. Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001).

    CAS  PubMed  Google Scholar 

  97. Tuveson, D. A. et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 20, 5054–5058 (2001).

    CAS  PubMed  Google Scholar 

  98. Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell 161, 1681–1696 (2015).

  99. Parums, D. V. Current status of targeted therapy in non-small cell lung cancer. Drugs Today (Barc.) 50, 503–525 (2014).

    CAS  Google Scholar 

  100. Poulikakos, P. I. & Rosen, N. Mutant BRAF melanomas — dependence and resistance. Cancer Cell 19, 11–15 (2011).

    CAS  PubMed  Google Scholar 

  101. Ahuja, N., Sharma, A. R. & Baylin, S. B. Epigenetic therapeutics: a new weapon in the war against cancer. Annu. Rev. Med. 67, 73–89 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Azad, N., Zahnow, C. A., Rudin, C. M. & Baylin, S. B. The future of epigenetic therapy in solid tumours — lessons from the past. Nat. Rev. Clin. Oncol. 10, 256–266 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Egger, G., Liang, G., Aparicio, A. & Jones, P. A. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457–463 (2004).

    CAS  PubMed  Google Scholar 

  104. Cameron, E. E., Bachman, K. E., Myohanen, S., Herman, J. G. & Baylin, S. B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat. Genet. 21, 103–107 (1999). An early paper demonstrating the feasibility of combination therapies with epigenetic drugs.

    CAS  PubMed  Google Scholar 

  105. Bird, A. P. & Wolffe, A. P. Methylation-induced repression — belts, braces, and chromatin. Cell 99, 451–454 (1999).

    CAS  PubMed  Google Scholar 

  106. Eden, S., Hashimshony, T., Keshet, I., Cedar, H. & Thorne, A. W. DNA methylation models histone acetylation. Nature 394, 842 (1998).

    CAS  PubMed  Google Scholar 

  107. Cai, Y. et al. The NuRD complex cooperates with DNMTs to maintain silencing of key colorectal tumor suppressor genes. Oncogene 33, 2157–2168 (2014).

    CAS  PubMed  Google Scholar 

  108. Suzuki, H. et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat. Genet. 31, 141–149 (2002).

    CAS  PubMed  Google Scholar 

  109. Bradner, J. E. et al. Chemical phylogenetics of histone deacetylases. Nat. Chem. Biol. 6, 238–243 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Chai, G. et al. HDAC inhibitors act with 5-aza-2′-deoxycytidine to inhibit cell proliferation by suppressing removal of incorporated abases in lung cancer cells. PLoS ONE 3, e2445 (2008).

    PubMed  PubMed Central  Google Scholar 

  111. Luszczek, W., Cheriyath, V., Mekhail, T. M. & Borden, E. C. Combinations of DNA methyltransferase and histone deacetylase inhibitors induce DNA damage in small cell lung cancer cells: correlation of resistance with IFN-stimulated gene expression. Mol. Cancer Ther. 9, 2309–2321 (2010).

    CAS  PubMed  Google Scholar 

  112. Zhu, W. G., Lakshmanan, R. R., Beal, M. D. & Otterson, G. A. DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. Cancer Res. 61, 1327–1333 (2001).

    CAS  PubMed  Google Scholar 

  113. Zhu, W. G. & Otterson, G. A. The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr. Med. Chem. Anticancer Agents 3, 187–199 (2003).

    CAS  PubMed  Google Scholar 

  114. Prebet, T. et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. J. Clin. Oncol. 32, 1242–1248 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Garcia-Manero, G. et al. Phase I/II study of MGCD0103, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in higher-risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Blood Abstr. 110, 444 (2007).

    Google Scholar 

  116. Silverman, L. R. et al. A phase I trial of the epigenetic modulators vorinostat, in combination with azacitidine (azaC) in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML): a study of the New York Cancer Consortium. Blood Abstr. 112, 3656 (2008). This article underlines the potential for combination therapies in patients.

    Google Scholar 

  117. Juergens, R. A. et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 1, 598–607 (2011). This paper presents preliminary evidence for the concept of 'priming' patients with DNMTi before immune checkpoint therapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Wrangle, J. et al. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget 4, 2067–2079 (2013).

    PubMed  PubMed Central  Google Scholar 

  119. Benson, E. A., Skaar, T. C., Liu, Y., Nephew, K. P. & Matei, D. Carboplatin with decitabine therapy, in recurrent platinum resistant ovarian cancer, alters circulating miRNAs concentrations: a pilot study. PLoS ONE 10, e0141279 (2015).

    PubMed  PubMed Central  Google Scholar 

  120. Fang, F. et al. A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer. Cancer 116, 4043–4053 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Fang, F. et al. The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clin. Cancer Res. 20, 6504–6516 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Fang, F. et al. Decitabine reactivated pathways in platinum resistant ovarian cancer. Oncotarget 5, 3579–3589 (2014).

    PubMed  PubMed Central  Google Scholar 

  123. Matei, D. et al. Epigenetic resensitization to platinum in ovarian cancer. Cancer Res. 72, 2197–2205 (2012). A key trial demonstrating the potential for DNMTi to reverse drug resistance in the clinic.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Matei, D. E. & Nephew, K. P. Epigenetic therapies for chemoresensitization of epithelial ovarian cancer. Gynecol. Oncol. 116, 195–201 (2010).

    CAS  PubMed  Google Scholar 

  125. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Sharma, P. & Allison, J. P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Drake, C. G., Jaffee, E. & Pardoll, D. M. Mechanisms of immune evasion by tumors. Adv. Immunol. 90, 51–81 (2006).

    CAS  PubMed  Google Scholar 

  129. Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    CAS  PubMed  Google Scholar 

  130. Heninger, E., Krueger, T. E. & Lang, J. M. Augmenting antitumor immune responses with epigenetic modifying agents. Front. Immunol. 6, 29 (2015).

    PubMed  PubMed Central  Google Scholar 

  131. Karpf, A. R. A potential role for epigenetic modulatory drugs in the enhancement of cancer/germ-line antigen vaccine efficacy. Epigenetics 1, 116–120 (2006).

    PubMed  PubMed Central  Google Scholar 

  132. Chiappinelli, K. B., Zahnow, C. A., Ahuja, N. & Baylin, S. B. Combining epigenetic and immunotherapy to combat cancer. Cancer Res. 76, 1683–1689 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Dear, A. E. Epigenetic modulators and the new immunotherapies. N. Engl. J. Med. 374, 684–686 (2016).

    CAS  PubMed  Google Scholar 

  134. Jin, L. et al. Loss of LSD1 (lysine-specific demethylase 1) suppresses growth and alters gene expression of human colon cancer cells in a p53- and DNMT1 (DNA methyltransferase 1)-independent manner. Biochem. J. 449, 459–468 (2013).

    CAS  PubMed  Google Scholar 

  135. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    CAS  PubMed  Google Scholar 

  136. Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Bradner, J. New targets for hematologic malignancies. Clin. Adv. Hematol. Oncol. 11, 375–376 (2013).

    PubMed  Google Scholar 

  138. Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).

    CAS  PubMed  Google Scholar 

  139. Fiskus, W. et al. Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol. Cancer Ther. 13, 1142–1154 (2014).

    CAS  PubMed  Google Scholar 

  140. Allis, C. D., Caparros, M.-L., Jenuwein, T., Reinberg, D. & Lachner, M. Epigenetics (Cold Spring Harbor Laboratory Press, 2015).

    Google Scholar 

  141. Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012).

    CAS  PubMed  Google Scholar 

  142. Berman, B. P. et al. Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat. Genet. 44, 40–46 (2012). This paper defines the distribution of cytosine methylation in uncultured human cancers.

    CAS  Google Scholar 

Download references

Acknowledgements

Research funding was provided by the Van Andel Research Institute–Stand Up To Cancer (SU2C) Epigenetics Dream Team, of which the authors are members. SU2C is a programme of the Entertainment Industry Foundation (EIF), administered by the American Association for Cancer Research (AACR). P.A.J. is supported by the US National Cancer Institute (RO1 CA082422). J.-P.J.I. is supported by the US National Institutes of Health (NIH) (CA158112 and CA100632) and by a grant from the Ellison Medical Foundation. He is also an American Cancer Society Clinical Research Professor supported by a generous gift from the F.M. Kirby Foundation. S.B. receives support from the NIH (R01 CA170550), the EIF Jim Toth Sr. Breakthrough Lung Cancer Research Award, the Rising Tide Foundation and SU2C (SU2C-AACR-CT0109).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peter A. Jones.

Ethics declarations

Competing interests

P.A.J. is a paid consultant for Zymo Corporation. S.B. has consulted for Celgene Corporation, Astex Pharmaceuticals, Chugai Pharmaceuticals, Merck–Pfizer and Merck & Co. regarding some of the work mentioned. J.-P.J.I. is a consultant for and has received research support from Astex Pharmaceuticals.

Related links

PowerPoint slides

Glossary

Writers

Enzymes that apply covalent modifications, such as methyl or acetyl groups, to specific amino acids on histones.

Readers

Proteins that can recognize specific modifications on histones at defined positions in the protein backbone.

Plasticity

The reversibility of epigenetic marks on DNA and proteins.

Erasers

Enzymes that can remove specific modifications at defined sites on DNA or histones.

TET family

The ten-eleven translocation family of α-ketoglutarate-dependent dioxygenases catalyse the oxidation of 5-methlcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further products. Genes encoding these enzymes are frequently mutated in human cancers.

Driver

A gene in which the activation or deactivation of expression is causally related to the establishment of the malignant state.

Genomic medicines

Drugs that have wide-ranging effects on the epigenome.

Precision medicine

The use of drugs to target specific abnormalities identified in a patient.

Synthetic lethality

A relationship between two genes in which the combined inactivation of the genes results in cell death, whereas the inactivation of either gene alone has no effect. It can also refer to a gene whose perturbation only results in cell death in the presence of a particular cellular feature (for example, a mutation).

LINEs

(Long interspersed nuclear elements). Highly repetitious elements that make up a considerable portion of the human genome; their methylation status can be used as a surrogate for overall genomic methylation.

Alu elements

Interspersed DNA sequences of about 300bp that belong to the short interspersed element (SINE) family and are found in the genome of primates.

Frontline therapy

The use of a drug early in treatment before other drugs have been used.

CCCTC-binding factor sites

(CTCF sites). Binding sites for the CTCF transcription factor, which is involved in transcriptional activation, insulator activity and regulation of chromatin architecture.

Cancer testis antigens

(CTAs). A group of proteins expressed during male germ cell development, which are silenced in normal cells and may become re-expressed ectopically in cancers. Many are highly immunogenic.

Monotherapies

The use of a single drug to treat a malignancy.

Immune checkpoint therapy

The use of antibodies that target regulatory pathways in T cells to enhance antitumour immune response.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jones, P., Issa, JP. & Baylin, S. Targeting the cancer epigenome for therapy. Nat Rev Genet 17, 630–641 (2016). https://doi.org/10.1038/nrg.2016.93

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg.2016.93

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer