1932

Abstract

The past 15 years have seen an explosion of discoveries related to the cellular regulation of phenotypes through epigenetic mechanisms. This regulation provides a software that packages DNA, without changing the primary base sequence, to establish heritable patterns of gene expression. In cancer, many aspects of the epigenome, controlled by DNA methylation, chromatin, and nucleosome positioning, are altered as one means by which tumor cells maintain abnormal states of self-renewal at the expense of normal maturation. Epigenetic and genetic abnormalities thus collaborate in cancer initiation and progression, as exemplified by frequent mutations in genes encoding proteins that control the epigenome. There is growing emphasis on using epigenetic therapies to reprogram neoplastic cells toward a normal state. Many agents targeting epigenetic regulation are under development and entering clinical trials. This review highlights the promise that epigenetic therapy, often in combination with other therapies, will become a potent tool for cancer management over the next decade.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-111314-035900
2016-01-14
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/med/67/1/annurev-med-111314-035900.html?itemId=/content/journals/10.1146/annurev-med-111314-035900&mimeType=html&fmt=ahah

Literature Cited

  1. Masters GA, Krilov L, Bailey HH. 1.  et al. 2015. Clinical cancer advances 2015: annual report on progress against cancer from the American Society of Clinical Oncology. J. Clin. Oncol. 33:786–809 [Google Scholar]
  2. Sun Y, Ma L. 2.  2015. The emerging molecular machinery and therapeutic targets of metastasis. Trends Pharmacol. Sci. 36:349–59 [Google Scholar]
  3. Mwenifumbo JC, Marra MA. 3.  2013. Cancer genome-sequencing study design. Nat. Rev. Genet. 14:321–32 [Google Scholar]
  4. Allis C, Jenuwein T, Reinberg D, Caparros M. 4.  2015. Epigenetics Cold Spring Harbor, NY: Cold Spring Harbor Lab. Press, 2nd ed..
  5. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. 5.  2009. An operational definition of epigenetics. Genes Dev. 23:781–83 [Google Scholar]
  6. Messerschmidt DM, Knowles BB, Solter D. 9.  2014. DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev. 28:812–28 [Google Scholar]
  7. Baylin SB, Jones PA. 6.  2011. A decade of exploring the cancer epigenome—biological and translational implications. Nat. Rev. Cancer 11:726–34 [Google Scholar]
  8. Jones PA, Baylin SB. 7.  2007. The epigenomics of cancer. Cell 128:683–92 [Google Scholar]
  9. Sandoval J, Esteller M. 8.  2012. Cancer epigenomics: beyond genomics. Curr. Opin. Genet. Dev. 22:50–55 [Google Scholar]
  10. Garraway LA, Lander ES. 10.  2013. Lessons from the cancer genome. Cell 153:17–37 [Google Scholar]
  11. Shen H, Laird PW. 11.  2013. Interplay between the cancer genome and epigenome. Cell 153:38–55 [Google Scholar]
  12. You JS, Jones PA. 12.  2012. Cancer genetics and epigenetics: two sides of the same coin?. Cancer Cell 22:9–20 [Google Scholar]
  13. Ahuja N, Easwaran H, Baylin SB. 13.  2014. Harnessing the potential of epigenetic therapy to target solid tumors. J. Clin. Investig. 124:56–63 [Google Scholar]
  14. Clevers H. 14.  2006. Wnt/beta-catenin signaling in development and disease. Cell 127:469–80 [Google Scholar]
  15. Jones PA, Taylor SM. 15.  1980. Cellular differentiation, cytidine analogs and DNA methylation. Cell 20:85–93 [Google Scholar]
  16. Silverman LR, Demakos EP, Peterson BL. 16.  et al. 2002. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J. Clin. Oncol. 20:2429–40 [Google Scholar]
  17. Tsai HC, Li H, Van Neste L. 17.  et al. 2012. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21:430–46 [Google Scholar]
  18. Kaminskas E, Farrell AT, Wang YC. 18.  et al. 2005. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist 10:176–82 [Google Scholar]
  19. 19. The ENCODE Project Consortium 2015. An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74 [Google Scholar]
  20. Schneider R, Grosschedl R. 20.  2007. Dynamics and interplay of nuclear architecture, genome organization, and gene expression. Genes Dev. 21:3027–43 [Google Scholar]
  21. 21. Cancer Genome Atlas Network 2015. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517:576–82 [Google Scholar]
  22. Liu X, McEachron TA, Schwartzentruber J, Wu G. 22.  2014. Histone H3 mutations in pediatric brain tumors. Cold Spring Harb. Perspect. Biol. 6:a018689 [Google Scholar]
  23. Jones S, Wang TL, Shih IeM. 23.  et al. 2010. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330:228–31 [Google Scholar]
  24. Wu JN, Roberts CW. 24.  2013. ARID1A mutations in cancer: another epigenetic tumor suppressor?. Cancer Discov. 3:35–43 [Google Scholar]
  25. Bestor TH, Edwards JR, Boulard M. 25.  2015. Notes on the role of dynamic DNA methylation in mammalian development. PNAS 112:6796–99 [Google Scholar]
  26. Millan MJ. 26.  2013. An epigenetic framework for neurodevelopmental disorders: from pathogenesis to potential therapy. Neuropharmacology 68:2–82 [Google Scholar]
  27. Chendhore SV, Sleiman S, Coppola G. 27.  2013. Epigenetics of Alzheimer's disease and frontotemporal dementia. Neurotherapeutics 10:709–21 [Google Scholar]
  28. Robertson KD. 28.  2001. DNA methylation, methyltransferases, and cancer. Oncogene 20:3139–55 [Google Scholar]
  29. Spruijt CG, Gnerlich F, Smits AH. 29.  et al. 2013. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152:1146–59 [Google Scholar]
  30. Pastor WA, Aravind L, Rao A. 30.  2013. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat. Rev. Mol. Cell Biol. 14:341–56 [Google Scholar]
  31. Berger SL. 31.  2007. The complex language of chromatin regulation during transcription. Nature 447:407–12 [Google Scholar]
  32. Seto E, Yoshida M. 32.  2014. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 6:a018713 [Google Scholar]
  33. Morey L, Helin K. 33.  2010. Polycomb group protein-mediated repression of transcription. Trends Biochem. Sci. 35:323–32 [Google Scholar]
  34. Schwartz YB, Pirrotta V. 34.  2013. A new world of Polycombs: unexpected partnerships and emerging functions. Nat. Rev. Genet. 14:853–64 [Google Scholar]
  35. Bracken AP, Helin K. 35.  2009. Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat. Rev. Cancer 9:773–84 [Google Scholar]
  36. Hock H. 36.  2012. A complex Polycomb issue: the two faces of EZH2 in cancer. Genes Dev. 26:751–55 [Google Scholar]
  37. Lee JT. 37.  2012. Epigenetic regulation by long noncoding RNAs. Science 338:1435–39 [Google Scholar]
  38. Yu W, Gius D, Onyango P. 38.  et al. 2008. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451:202–6 [Google Scholar]
  39. Di Ruscio A, Ebralidze AK, Benoukraf T. 39.  et al. 2013. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 503:371–76 [Google Scholar]
  40. Issa JP. 40.  2005. DNA methylation in the treatment of hematologic malignancies. Clin. Adv. Hematol. Oncol. 3:684–86 [Google Scholar]
  41. Silverman LR, Mufti GJ. 41.  2005. Methylation inhibitor therapy in the treatment of myelodysplastic syndrome. Nat. Clin. Pract. Oncol. 2:Suppl. 1S12–23 [Google Scholar]
  42. Azad N, Zahnow CA, Rudin CM, Baylin SB. 42.  2013. The future of epigenetic therapy in solid tumours—lessons from the past. Nat. Rev. Clin. Oncol. 10:256–66 [Google Scholar]
  43. Ghoshal K, Datta J, Majumder S. 43.  et al. 2005. 5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal. Mol. Cell. Biol. 25:4727–41 [Google Scholar]
  44. Kelly TK, De Carvalho DD, Jones PA. 44.  2010. Epigenetic modifications as therapeutic targets. Nat. Biotechnol. 28:1069–78 [Google Scholar]
  45. Silverman LR, Fenaux P, Mufti GJ. 45.  et al. 2011. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer 117:2697–702 [Google Scholar]
  46. Chuang JC, Warner SL, Vollmer D. 46.  et al. 2010. S110, a 5-Aza-2′-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol. Cancer Ther. 9:1443–50 [Google Scholar]
  47. Lubbert M. 47.  2000. DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr. Top. Microbiol. Immunol. 249:135–64 [Google Scholar]
  48. West AC, Johnstone RW. 48.  2014. New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest. 124:30–39 [Google Scholar]
  49. Bose P, Dai Y, Grant S. 49.  2014. Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights. Pharmacol. Ther. 143:323–36 [Google Scholar]
  50. Robert C, Rassool FV. 50.  2012. HDAC inhibitors: roles of DNA damage and repair. Adv. Cancer Res. 116:87–129 [Google Scholar]
  51. Cai Y, Geutjes EJ, de Lint K. 51.  et al. 2013. The NuRD complex cooperates with DNMTs to maintain silencing of key colorectal tumor suppressor genes. Oncogene 33:2157–68 [Google Scholar]
  52. Cameron EE, Bachman KE, Myohanen S. 52.  et al. 1999. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat. Genet. 21:103–7 [Google Scholar]
  53. Suzuki H, Watkins DN, Jair KW. 53.  et al. 2004. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat. Genet. 36:417–22 [Google Scholar]
  54. Garcia-Manero G. 54.  2008. Demethylating agents in myeloid malignancies. Curr. Opin. Oncol. 20:705–10 [Google Scholar]
  55. Gore SD, Jiemjit A, Silverman LB. 55.  et al. 2006. Combined methyltransferase/histone deacetylase inhibition with 5-azacitidine and MS-275 in patients with MDS, CMMoL and AML: clinical response, histone acetylation and DNA damage. Blood (ASH Annu. Meet. Abstr.) 108:517 [Google Scholar]
  56. Maslak P, Chanel S, Camacho LH. 56.  et al. 2006. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia 20:212–17 [Google Scholar]
  57. Voso MT, Santini V, Finelli C. 57.  et al. 2009. Valproic acid at therapeutic plasma levels may increase 5-azacytidine efficacy in higher risk myelodysplastic syndromes. Clin. Cancer Res. 15:5002–7 [Google Scholar]
  58. Prebet T, Sun Z, Figueroa ME. 58.  et al. 2014. 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. 32:1242–48 [Google Scholar]
  59. Juergens RA, Wrangle J, Vendetti FP. 59.  et al. 2011. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 1:598–607 [Google Scholar]
  60. Sharma SV, Lee DY, Li B. 60.  et al. 2010. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141:69–80 [Google Scholar]
  61. Roesch A, Fukunaga-Kalabis M, Schmidt EC. 61.  et al. 2010. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141:583–94 [Google Scholar]
  62. Ramalingam SS, Maitland ML, Frankel P. 62.  et al. 2010. Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J. Clin. Oncol. 28:56–62 [Google Scholar]
  63. Fu S, Hu W, Iyer R. 63.  et al. 2011. Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. Cancer 117:1661–69 [Google Scholar]
  64. San-Miguel JF, Hungria VT, Yoon SS. 64.  et al. 2014. 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. 15:1195–206 [Google Scholar]
  65. Yardley DA, Ismail-Khan RR, Melichar B. 65.  et al. 2013. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J. Clin. Oncol. 31:2128–35 [Google Scholar]
  66. Wrangle J, Wang W, Koch A. 66.  et al. 2013. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget 4:2067–79 [Google Scholar]
  67. Chiappinelli KB, Strissel PL, Desrichard A. 67.  et al. 2015. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162:974–86 [Google Scholar]
  68. Krummel MF, Allison JP. 68.  1995. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182:459–65 [Google Scholar]
  69. Pardoll DM. 69.  2012. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12:252–64 [Google Scholar]
  70. Topalian SL, Hodi FS, Brahmer JR. 70.  et al. 2012. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366:2443–54 [Google Scholar]
  71. Brahmer J, Reckamp KL, Baas P. 71.  et al. 2015. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373:123–35 [Google Scholar]
  72. Hodi FS, O'Day SJ, McDermott DF. 72.  et al. 2010. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363:711–23 [Google Scholar]
  73. Brahmer JR, Tykodi SS, Chow LQ. 73.  et al. 2012. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366:2455–65 [Google Scholar]
  74. Garon EB, Rizvi NA, Hui R. 74.  et al. 2015. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372:2018–28 [Google Scholar]
  75. 75.  Deleted in proof
  76. Li H, Chiappinelli KB, Guzzetta AA. 76.  et al. 2014. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 5:587–98 [Google Scholar]
  77. Karpf AR, Lasek AW, Ririe TO. 77.  et al. 2004. Limited gene activation in tumor and normal epithelial cells treated with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine. Mol. Pharmacol. 65:18–27 [Google Scholar]
  78. Khan AN, Tomasi TB. 78.  2008. Histone deacetylase regulation of immune gene expression in tumor cells. Immunol. Res. 40:164–78 [Google Scholar]
  79. Roulois D, Helen Loo Yau RS, Wang Y. 79.  et al. 2015. Low dose DNA-demethylating agents target colorectal cancer-initiating cells by activation of MDA5/MAVS/IRF7 pathway. Cell 162:961–73 [Google Scholar]
  80. Rizvi NA, Hellmann MD, Snyder A. 80.  et al. 2015. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–28 [Google Scholar]
  81. Snyder A, Makarov V, Merghoub T. 81.  et al. 2014. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371:2189–99 [Google Scholar]
  82. Dawson MA, Kouzarides T. 82.  2012. Cancer epigenetics: from mechanism to therapy. Cell 150:12–27 [Google Scholar]
  83. Tanaka M, Roberts JM, Qi J, Bradner JE. 83.  2015. Inhibitors of emerging epigenetic targets for cancer therapy: a patent review (2010–2014). Pharm. Pat Anal. 4:261–84 [Google Scholar]
  84. Figueroa ME, Lugthart S, Li Y. 84.  et al. 2010. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 17:13–27 [Google Scholar]
  85. Lu C, Ward PS, Kapoor GS. 85.  et al. 2012. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483:474–78 [Google Scholar]
  86. Turcan S, Rohle D, Goenka A. 86.  et al. 2012. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479–83 [Google Scholar]
  87. Venneti S, Felicella MM, Coyne T. 87.  et al. 2013. Histone 3 lysine 9 trimethylation is differentially associated with isocitrate dehydrogenase mutations in oligodendrogliomas and high-grade astrocytomas. J. Neuropathol. Exp. Neurol. 72:298–306 [Google Scholar]
  88. Noushmehr H, Weisenberger DJ, Diefes K. 88.  et al. 2010. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510–22 [Google Scholar]
  89. Yeng FH, Molly NH, Louis JM. 89.  2015. Oxygen concentration controls epigenetic effects in models of familial paraganglioma. PLoS ONE 10:e0127471 [Google Scholar]
  90. Knutson SK, Wigle TJ, Warholic NM. 90.  et al. 2012. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8:890–96 [Google Scholar]
  91. McCabe MT, Ott HM, Ganji G. 91.  et al. 2012. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492:108–12 [Google Scholar]
  92. Daigle SR, Olhava EJ, Therkelsen CA. 92.  et al. 2011. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20:53–65 [Google Scholar]
  93. Caskey CT. 93.  2010. Using genetic diagnosis to determine individual therapeutic utility. Annu. Rev. Med. 61:1–15 [Google Scholar]
/content/journals/10.1146/annurev-med-111314-035900
Loading
/content/journals/10.1146/annurev-med-111314-035900
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error