1932

Abstract

Alterations of genes regulating epigenetic processes are frequently found as cancer drivers and may cause widespread alterations of DNA methylation, histone modification patterns, or chromatin structure that disrupt normal patterns of gene expression. Because of the inherent reversibility of epigenetic changes, inhibitors targeting these processes are promising anticancer strategies. Small molecules targeting epigenetic regulators have been developed recently, and clinical trials of these agents are under way for hematologic malignancies and solid tumors. In this review, we describe how the writers, readers, and erasers of epigenetic marks are dysregulated in cancer and summarize the development of therapies targeting these mechanisms.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010716-105106
2018-01-06
2024-06-13
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/58/1/annurev-pharmtox-010716-105106.html?itemId=/content/journals/10.1146/annurev-pharmtox-010716-105106&mimeType=html&fmt=ahah

Literature Cited

  1. Kornberg RD. 1.  1974. Chromatin structure: a repeating unit of histones and DNA. Science 184:868–71 [Google Scholar]
  2. Richmond TJ, Finch JT, Rushton B, Rhodes D, Klug A. 2.  1984. Structure of the nucleosome core particle at 7 Å resolution. Nature 311:532–37 [Google Scholar]
  3. Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ. 3.  1997. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389:251–60 [Google Scholar]
  4. Brownell JE, Zhou J, Ranalli T, Kobayashi R, Edmondson DG. 4.  et al. 1996. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84:843–51 [Google Scholar]
  5. Luger K, Richmond TJ. 5.  1998. The histone tails of the nucleosome. Curr. Opin. Genet. Dev. 8:140–46 [Google Scholar]
  6. Steger DJ, Workman JL. 6.  1996. Remodeling chromatin structures for transcription: What happens to the histones?. BioEssays 18:875–84 [Google Scholar]
  7. Saxonov S, Berg P, Brutlag DL. 7.  2006. A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. PNAS 103:1412–17 [Google Scholar]
  8. Illingworth RS, Gruenewald-Schneider U, Webb S, Kerr AR, James KD. 8.  et al. 2010. Orphan CpG islands identify numerous conserved promoters in the mammalian genome. PLOS Genet 6:e1001134 [Google Scholar]
  9. Zilberman D, Gehring M, Tran RK, Ballinger T, Henikoff S. 9.  2007. Genome-wide analysis of Arabidopsis thaliana DNA methylation uncovers an interdependence between methylation and transcription. Nat. Genet. 39:61–69 [Google Scholar]
  10. Herman JG, Baylin SB. 10.  2003. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 349:2042–54 [Google Scholar]
  11. Rodriguez C, Borgel J, Court F, Cathala G, Forné T, Piette J. 11.  2010. CTCF is a DNA methylation-sensitive positive regulator of the INK/ARF locus. Biochem. Biophys. Res. Commun. 392:129–34 [Google Scholar]
  12. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA. 12.  et al. 2014. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505:495–501 [Google Scholar]
  13. Timp W, Feinberg AP. 13.  2013. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat. Rev. Cancer 13:497–510 [Google Scholar]
  14. Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X. 14.  et al. 2000. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J. Natl. Cancer Inst. 92:564–69 [Google Scholar]
  15. Greger V, Passarge E, Hopping W, Messmer E, Horsthemke B. 15.  1989. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum. Genet. 83:155–58 [Google Scholar]
  16. Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E. 16.  et al. 1995. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat. Med. 1:686–92 [Google Scholar]
  17. Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC. 17.  1993. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 82:1820–28 [Google Scholar]
  18. Nishigaki M, Aoyagi K, Danjoh I, Fukaya M, Yanagihara K. 18.  et al. 2005. Discovery of aberrant expression of R-RAS by cancer-linked DNA hypomethylation in gastric cancer using microarrays. Cancer Res 65:2115–24 [Google Scholar]
  19. Zhou H, Chen WD, Qin X, Lee K, Liu L. 19.  et al. 2001. MMTV promoter hypomethylation is linked to spontaneous and MNU associated c-neu expression and mammary carcinogenesis in MMTV c-neu transgenic mice. Oncogene 20:6009–17 [Google Scholar]
  20. Watt PM, Kumar R, Kees UR. 20.  2000. Promoter demethylation accompanies reactivation of the HOX11 proto-oncogene in leukemia. Genes Chromosomes Cancer 29:371–77 [Google Scholar]
  21. Okano M, Bell DW, Haber DA, Li E. 21.  1999. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–57 [Google Scholar]
  22. Bostick M, Kim JK, Esteve PO, Clark A, Pradhan S, Jacobsen SE. 22.  2007. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317:1760–64 [Google Scholar]
  23. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T. 23.  et al. 2010. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363:2424–33 [Google Scholar]
  24. Yan XJ, Xu J, Gu ZH, Pan CM, Lu G. 24.  et al. 2011. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat. Genet. 43:309–15 [Google Scholar]
  25. Russler-Germain DA, Spencer DH, Young MA, Lamprecht TL, Miller CA. 25.  et al. 2014. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell 25:442–54 [Google Scholar]
  26. Santi DV, Norment A, Garrett CE. 26.  1984. Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. PNAS 81:6993–97 [Google Scholar]
  27. Ghoshal K, Datta J, Majumder S, Bai S, Kutay H. 27.  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]
  28. Schaefer M, Hagemann S, Hanna K, Lyko F. 28.  2009. Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines. Cancer Res 69:8127–32 [Google Scholar]
  29. Ley TJ, DeSimone J, Anagnou NP, Keller GH, Humphries RK. 29.  et al. 1982. 5-Azacytidine selectively increases γ-globin synthesis in a patient with β+ thalassemia. N. Engl. J. Med. 307:1469–75 [Google Scholar]
  30. Ginder GD, Whitters MJ, Pohlman JK. 30.  1984. Activation of a chicken embryonic globin gene in adult erythroid cells by 5-azacytidine and sodium butyrate. PNAS 81:3954–58 [Google Scholar]
  31. Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. 31.  1999. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat. Genet. 21:103–7 [Google Scholar]
  32. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC. 32.  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]
  33. Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M. 33.  et al. 2006. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106:1794–803 [Google Scholar]
  34. Yoo CB, Jeong S, Egger G, Liang G, Phiasivongsa P. 34.  et al. 2007. Delivery of 5-aza-2′-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res 67:6400–8 [Google Scholar]
  35. Tsai HC, Li H, Van Neste L, Cai Y, Robert C. 35.  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]
  36. Palii SS, Van Emburgh BO, Sankpal UT, Brown KD, Robertson KD. 36.  2008. DNA methylation inhibitor 5-aza-2′-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol. Cell. Biol. 28:752–71 [Google Scholar]
  37. Gore SD, Baylin S, Sugar E, Carraway H, Miller CB. 37.  et al. 2006. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66:6361–69 [Google Scholar]
  38. Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T. 38.  2000. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat. Genet. 24:88–91 [Google Scholar]
  39. Fuks F, Hurd PJ, Deplus R, Kouzarides T. 39.  2003. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res 31:2305–12 [Google Scholar]
  40. Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A. 40.  et al. 2015. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162:961–73 [Google Scholar]
  41. Tefferi A, Lasho TL, Abdel-Wahab O, Guglielmelli P, Patel J. 41.  et al. 2010. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia 24:1302–9 [Google Scholar]
  42. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D. 42.  et al. 2011. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J. Pathol. 224:334–43 [Google Scholar]
  43. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA. 43.  et al. 2009. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360:765–73 [Google Scholar]
  44. Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR. 44.  et al. 2012. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 17:72–79 [Google Scholar]
  45. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD. 45.  et al. 2010. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17:225–34 [Google Scholar]
  46. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S. 46.  et al. 2009. Mutation in TET2 in myeloid cancers. N. Engl. J. Med. 360:2289–301 [Google Scholar]
  47. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J. 47.  et al. 2010. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553–67 [Google Scholar]
  48. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S. 48.  et al. 2012. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483:474–78 [Google Scholar]
  49. Carbonneau M, Gagné LM, Lalonde ME, Germain MA, Motorina A. 49.  et al. 2016. The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway. Nat. Commun. 7:12700 [Google Scholar]
  50. Stein EM, DiNardo C, Altman JK, Collins R, DeAngelo DJ. 50.  et al. 2015. Safety and efficacy of AG-221, a potent inhibitor of mutant IDH2 that promotes differentiation of myeloid cells in patients with advanced hematologic malignancies: results of a Phase 1/2 trial. Blood 126:323 [Google Scholar]
  51. Wang J, Iwasaki H, Krivtsov A, Febbo PG, Thorner AR. 51.  et al. 2005. Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease. EMBO J 24:368–81 [Google Scholar]
  52. Ogiwara H, Sasaki M, Mitachi T, Oike T, Higuchi S. 52.  et al. 2016. Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality by apoptotic cell death due to abrogation of MYC expression. Cancer Discov 6:430–45 [Google Scholar]
  53. Sobulo OM, Borrow J, Tomek R, Reshmi S, Harden A. 53.  et al. 1997. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3). PNAS 94:8732–37 [Google Scholar]
  54. Borrow J, Stanton VP Jr., Andresen JM, Becher R, Behm FG. 54.  et al. 1996. The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB–binding protein. Nat. Genet. 14:33–41 [Google Scholar]
  55. Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A. 55.  et al. 2011. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471:189–95 [Google Scholar]
  56. Kelly TJ, Qin S, Gottschling DE, Parthun MR. 56.  2000. Type B histone acetyltransferase Hat1p participates in telomeric silencing. Mol. Cell. Biol. 20:7051–58 [Google Scholar]
  57. Qin S, Parthun MR. 57.  2002. Histone H3 and the histone acetyltransferase Hat1p contribute to DNA double-strand break repair. Mol. Cell. Biol. 22:8353–65 [Google Scholar]
  58. Lai C, Lin C, Chao A. 58.  2016. HAT1 as a target for combination therapy with pazopanib and hyperthermia. J. Clin. Oncol. 341:Suppl. 5e17120 [Google Scholar]
  59. Xue K, Gu JJ, Zhang Q, Mavis C, Hernandez-Ilizaliturri FJ. 59.  et al. 2016. Vorinostat, a histone deacetylase (HDAC) inhibitor, promotes cell cycle arrest and re-sensitizes rituximab- and chemo-resistant lymphoma cells to chemotherapy agents. J. Cancer Res. Clin. Oncol. 142:379–87 [Google Scholar]
  60. Richon VM, Sandhoff TW, Rifkind RA, Marks PA. 60.  2000. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. PNAS 97:10014–19 [Google Scholar]
  61. Terui T, Murakami K, Takimoto R, Takahashi M, Takada K. 61.  et al. 2003. Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors. Cancer Res 63:8948–54 [Google Scholar]
  62. Lamonica JM, Vakoc CR, Blobel GA. 62.  2006. Acetylation of GATA-1 is required for chromatin occupancy. Blood 108:3736–38 [Google Scholar]
  63. Santo L, Hideshima T, Kung AL, Tseng JC, Tamang D. 63.  et al. 2012. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 119:2579–89 [Google Scholar]
  64. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE. 64.  et al. 2007. High-resolution profiling of histone methylations in the human genome. Cell 129:823–37 [Google Scholar]
  65. Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A. 65.  et al. 2009. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459:108–12 [Google Scholar]
  66. Krivtsov AV, Armstrong SA. 66.  2007. MLL translocations, histone modifications and leukaemia stem-cell development. Nat. Rev. Cancer 7:823–33 [Google Scholar]
  67. Bitoun E, Oliver PL, Davies KE. 67.  2007. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum. Mol. Genet. 16:92–106 [Google Scholar]
  68. Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J. 68.  et al. 2011. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20:66–78 [Google Scholar]
  69. Waters NJ, Daigle SR, Rehlaender BN, Basavapathruni A, Campbell CT. 69.  et al. 2015. Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target. J. Control. Release 220:758–65 [Google Scholar]
  70. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J. 70.  et al. 2010. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42:181–85 [Google Scholar]
  71. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C. 71.  et al. 2002. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419:624–29 [Google Scholar]
  72. Kleer CG, Cao Q, Varambally S, Shen R, Ota I. 72.  et al. 2003. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. PNAS 100:11606–11 [Google Scholar]
  73. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C. 73.  et al. 2010. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat. Genet. 42:722–26 [Google Scholar]
  74. Xu K, Wu ZJ, Groner AC, He HH, Cai C. 74.  et al. 2012. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 338:1465–69 [Google Scholar]
  75. Fiskus W, Wang Y, Sreekumar A, Buckley KM, Shi H. 75.  et al. 2009. Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood 114:2733–43 [Google Scholar]
  76. Qi W, Chan H, Teng L, Li L, Chuai S. 76.  et al. 2012. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. PNAS 109:21360–65 [Google Scholar]
  77. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C. 77.  et al. 2012. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492:108–12 [Google Scholar]
  78. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ. 78.  et al. 2012. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8:890–96 [Google Scholar]
  79. Kurmasheva RT, Sammons M, Favours E, Wu J, Kurmashev D. 79.  et al. 2017. Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. Pediatr. Blood Cancer 64:e26218 [Google Scholar]
  80. Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC. 80.  et al. 2014. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol. Cancer Ther. 13:842–54 [Google Scholar]
  81. van Haaften G, Dalgliesh GL, Davies H, Chen L, Bignell G. 81.  et al. 2009. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41:521–23 [Google Scholar]
  82. Kim KH, Kim W, Howard TP, Vazquez F, Tsherniak A. 82.  et al. 2015. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21:1491–96 [Google Scholar]
  83. Watanabe H, Soejima K, Yasuda H, Kawada I, Nakachi I. 83.  et al. 2008. Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells. Cancer Cell Int 8:15 [Google Scholar]
  84. Chen P, Yao JF, Huang RF, Zheng FF, Jiang XH. 84.  et al. 2015. Effect of BIX-01294 on H3K9me2 levels and the imprinted gene Snrpn in mouse embryonic fibroblast cells. Biosci. Rep. 35:e00257 [Google Scholar]
  85. Ceol CJ, Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA. 85.  et al. 2011. The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature 471:513–17 [Google Scholar]
  86. Rodriguez-Paredes M, Martinez de Paz A, Símo-Riudalbas L, Sayols S, Moutinho C. 86.  et al. 2014. Gene amplification of the histone methyltransferase SETDB1 contributes to human lung tumorigenesis. Oncogene 33:2807–13 [Google Scholar]
  87. Greiner D, Bonaldi T, Eskeland R, Roemer E, Imhof A. 87.  2005. Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3–9. Nat. Chem. Biol. 1:143–45 [Google Scholar]
  88. Wang L, Zhao Z, Meyer MB, Saha S, Yu M. 88.  et al. 2014. CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer Cell 25:21–36 [Google Scholar]
  89. Elakoum R, Gauchotte G, Oussalah A, Wissler MP, Clément-Duchêne C. 89.  et al. 2014. CARM1 and PRMT1 are dysregulated in lung cancer without hierarchical features. Biochimie 97:210–18 [Google Scholar]
  90. Tarighat SS, Santhanam R, Frankhouser D, Radomska HS, Lai H. 90.  et al. 2016. The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation. Leukemia 30:789–99 [Google Scholar]
  91. Yao R, Jiang H, Ma Y, Wang L, Wang L. 91.  et al. 2014. PRMT7 induces epithelial-to-mesenchymal transition and promotes metastasis in breast cancer. Cancer Res 74:5656–67 [Google Scholar]
  92. Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ. 92.  et al. 2015. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat. Chem. Biol. 11:432–37 [Google Scholar]
  93. Cheung N, Fung TK, Zeisig BB, Holmes K, Rane JK. 93.  et al. 2016. Targeting aberrant epigenetic networks mediated by PRMT1 and KDM4C in acute myeloid leukemia. Cancer Cell 29:32–48 [Google Scholar]
  94. Eram MS, Shen Y, Szewczyk MM, Wu H, Senisterra G. 94.  et al. 2016. A potent, selective, and cell-active inhibitor of human type I protein arginine methyltransferases. ACS Chem. Biol. 11:772–81 [Google Scholar]
  95. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR. 95.  et al. 2004. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–53 [Google Scholar]
  96. Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH. 96.  et al. 2006. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439:811–16 [Google Scholar]
  97. Sprussel A, Schulte JH, Weber S, Necke M, Handschke K. 97.  et al. 2012. Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia 26:2039–51 [Google Scholar]
  98. Metzger E, Wissmann M, Yin N, Muller JM, Schneider R. 98.  et al. 2005. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437:436–39 [Google Scholar]
  99. Metzger E, Willmann D, McMillan J, Forne I, Metzger P. 99.  et al. 2016. Assembly of methylated KDM1A and CHD1 drives androgen receptor–dependent transcription and translocation. Nat. Struct. Mol. Biol. 23:132–39 [Google Scholar]
  100. Schmidt DMZ, McCafferty DG. 100.  2007. trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry 46:4408–16 [Google Scholar]
  101. Maes T, Carceller E, Salas J, Ortega A, Buesa C. 101.  2015. Advances in the development of histone lysine demethylase inhibitors. Curr. Opin. Pharmacol. 23:52–60 [Google Scholar]
  102. Tresckow Bv, Gundermann S, Eichenauer DA, Aulitzky WE, Göbeler M. 102.  et al. 2014. First-in-human study of 4SC-202, a novel oral HDAC inhibitor in advanced hematologic malignancies (TOPAS study). J. Clin. Oncol. 32:8559 [Google Scholar]
  103. Heinemann B, Nielsen JM, Hudlebusch HR, Lees MJ, Larsen DV. 103.  et al. 2014. Inhibition of demethylases by GSK-J1/J4. Nature 514:E1–2 [Google Scholar]
  104. Ler LD, Ghosh S, Chai X, Thike AA, Heng HL. 104.  et al. 2017. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Sci. Transl. Med. 9:eaai8312 [Google Scholar]
  105. de Rooij JDE, Hollink IHIM, Arentsen-Peters STCJM, van Galen JF, Berna Beverloo H. 105.  et al. 2013. NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern. Leukemia 27:2280–88 [Google Scholar]
  106. Hancock RL, Dunne K, Walport LJ, Flashman E, Kawamura A. 106.  2015. Epigenetic regulation by histone demethylases in hypoxia. Epigenomics 7:791–811 [Google Scholar]
  107. Kim J, Daniel J, Espejo A, Lake A, Krishna M. 107.  et al. 2006. Tudor, MBT and chromo domains gauge the degree of lysine methylation. EMBO Rep 7:397–403 [Google Scholar]
  108. Yang Z, He N, Zhou Q. 108.  2008. Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol. Cell. Biol. 28:967–76 [Google Scholar]
  109. Shen C, Ipsaro JJ, Shi J, Milazzo JP, Wang E. 109.  et al. 2015. NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler. Mol. Cell 60:847–59 [Google Scholar]
  110. Yan J, Diaz J, Jiao J, Wang R, You J. 110.  2011. Perturbation of BRD4 protein function by BRD4-NUT protein abrogates cellular differentiation in NUT midline carcinoma. J. Biol. Chem. 286:27663–75 [Google Scholar]
  111. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M. 111.  et al. 2011. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478:529–33 [Google Scholar]
  112. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB. 112.  et al. 2010. Selective inhibition of BET bromodomains. Nature 468:1067–73 [Google Scholar]
  113. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H. 113.  et al. 2011. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478:524–28 [Google Scholar]
  114. Baratta MG, Schinzel AC, Zwang Y, Bandopadhayay P, Bowman-Colin C. 114.  et al. 2015. An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma. PNAS 112:232–37 [Google Scholar]
  115. Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M. 115.  et al. 2014. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510:278–82 [Google Scholar]
  116. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A. 116.  et al. 2015. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348:1376–81 [Google Scholar]
  117. Chaidos A, Caputo V, Gouvedenou K, Liu B, Marigo I. 117.  et al. 2014. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 123:697–705 [Google Scholar]
  118. Herold JM, Wigle TJ, Norris JL, Lam R, Korboukh VK. 118.  et al. 2011. Small-molecule ligands of methyl-lysine binding proteins. J. Med. Chem. 54:2504–11 [Google Scholar]
  119. James LI, Barsyte-Lovejoy D, Zhong N, Krichevsky L, Korboukh VK. 119.  et al. 2013. Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain. Nat. Chem. Biol. 9:184–91 [Google Scholar]
  120. Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M. 120.  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]
  121. Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L. 121.  et al. 2013. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet. 45:592–601 [Google Scholar]
  122. Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ. 122.  et al. 2013. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. PNAS 110:7922–27 [Google Scholar]
  123. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M. 123.  et al. 2009. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–40 [Google Scholar]
  124. Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S. 124.  et al. 2007. 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 [Google Scholar]
  125. Evens AM, Balasubramanian S, Vose JM, Harb W, Gordon LI. 125.  et al. 2016. A Phase I/II multicenter, open-label study of the oral histone deacetylase inhibitor abexinostat in relapsed/refractory lymphoma. Clin. Cancer Res. 22:1059–66 [Google Scholar]
  126. Lee HZ, Kwitkowski VE, Del Valle PL, Ricci MS, Saber H. 126.  et al. 2015. FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clin. Cancer Res. 21:2666–70 [Google Scholar]
  127. Kim KP, Park SJ, Kim JE, Hong YS, Lee JL. 127.  et al. 2015. First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies. Investig. New Drugs 33:1048–57 [Google Scholar]
  128. Banerji U, van Doorn L, Papadatos-Pastos D, Kristeleit R, Debnam P. 128.  et al. 2012. A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors. Clin. Cancer Res. 18:2687–94 [Google Scholar]
  129. Galloway TJ, Wirth LJ, Colevas AD, Gilbert J, Bauman JE. 129.  et al. 2015. A Phase I study of CUDC-101, a multitarget inhibitor of HDACs, EGFR, and HER2, in combination with chemoradiation in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 21:1566–73 [Google Scholar]
  130. Qian C, Lai CJ, Bao R, Wang DG, Wang J. 130.  et al. 2012. Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin. Cancer Res. 18:4104–13 [Google Scholar]
  131. Galli M, Salmoiraghi S, Golay J, Gozzini A, Crippa C. 131.  et al. 2010. A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma. Ann. Hematol. 89:185–90 [Google Scholar]
  132. Furlan A, Monzani V, Reznikov LL, Leoni F, Fossati G. 132.  et al. 2011. Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat). Mol. Med. 17:353–62 [Google Scholar]
  133. Zwergel C, Valente S, Jacob C, Mai A. 133.  2015. Emerging approaches for histone deacetylase inhibitor drug discovery. Expert Opin. Drug Discov. 10:599–613 [Google Scholar]
  134. Popat R, Brown SR, Flanagan L, Hall A, Gregory W. 134.  et al. 2016. Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial. Lancet Haematol 3:e572–80 [Google Scholar]
  135. Assouline SE, Nielsen TH, Yu S, Alcaide M, Chong L. 135.  et al. 2016. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood 128:185–94 [Google Scholar]
  136. Eigl BJ, North S, Winquist E, Finch D, Wood L. 136.  et al. 2015. A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195. Investig. New Drugs 33:969–76 [Google Scholar]
  137. Venugopal B, Baird R, Kristeleit RS, Plummer R, Cowan R. 137.  et al. 2013. A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors. Clin. Cancer Res. 19:4262–72 [Google Scholar]
  138. Brunetto AT, Ang JE, Lal R, Olmos D, Molife LR. 138.  et al. 2013. First-in-human, pharmacokinetic and pharmacodynamic phase I study of resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 19:5494–504 [Google Scholar]
  139. Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM. 139.  et al. 2007. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 25:3109–15 [Google Scholar]
  140. Shi Y, Dong M, Hong X, Zhang W, Feng J. 140.  et al. 2015. Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann. Oncol. 26:1766–71 [Google Scholar]
  141. Knipstein J, Gore L. 141.  2011. Entinostat for treatment of solid tumors and hematologic malignancies. Expert Opin. Investig. Drugs 20:1455–67 [Google Scholar]
  142. Younes A, Oki Y, Bociek RG, Kuruvilla J, Fanale M. 142.  et al. 2011. Mocetinostat for relapsed classical Hodgkin's lymphoma: an open-label, single-arm, phase 2 trial. Lancet Oncol 12:1222–28 [Google Scholar]
  143. Pauer LR, Olivares J, Cunningham C, Williams A, Grove W. 143.  et al. 2004. Phase I study of oral CI-994 in combination with carboplatin and paclitaxel in the treatment of patients with advanced solid tumors. Cancer Investig 22:886–96 [Google Scholar]
  144. Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J. 144.  et al. 2011. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 117:5827–34 [Google Scholar]
  145. Guzman ML, Yang N, Sharma KK, Balys M, Corbett CA. 145.  et al. 2014. Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: a novel potential strategy in acute myelogenous leukemia. Mol. Cancer Ther. 13:1979–90 [Google Scholar]
  146. Iannitti T, Palmieri B. 146.  2011. Clinical and experimental applications of sodium phenylbutyrate. Drugs R&D 11:227–49 [Google Scholar]
  147. Reid T, Valone F, Lipera W, Irwin D, Paroly W. 147.  et al. 2004. Phase II trial of the histone deacetylase inhibitor pivaloyloxymethyl butyrate (Pivanex, AN-9) in advanced non-small cell lung cancer. Lung Cancer 45:381–86 [Google Scholar]
  148. Bilen MA, Fu S, Falchook GS, Ng CS, Wheler JJ. 148.  et al. 2015. Phase I trial of valproic acid and lenalidomide in patients with advanced cancer. Cancer Chemother. Pharmacol. 75:869–74 [Google Scholar]
  149. Jo SY, Granowicz EM, Maillard I, Thomas D, Hess JL. 149.  2011. Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation. Blood 117:4759–68 [Google Scholar]
  150. Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L. 150.  et al. 2013. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122:1017–25 [Google Scholar]
  151. Yu W, Chory EJ, Wernimont AK, Tempel W, Scopton A. 151.  et al. 2012. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat. Commun. 3:1288 [Google Scholar]
  152. Tan J, Yang X, Zhuang L, Jiang X, Chen W. 152.  et al. 2007. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 21:1050–63 [Google Scholar]
  153. Konze KD, Ma A, Li F, Barsyte-Lovejoy D, Parton T. 153.  et al. 2013. An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1. ACS Chem. Biol. 8:1324–34 [Google Scholar]
  154. Chang Y, Zhang X, Horton JR, Upadhyay AK, Spannhoff A. 154.  et al. 2009. Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat. Struct. Mol. Biol. 16:312–17 [Google Scholar]
  155. Yuan Y, Wang Q, Paulk J, Kubicek S, Kemp MM. 155.  et al. 2012. A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. ACS Chem. Biol. 7:1152–57 [Google Scholar]
  156. Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A. 156.  et al. 2011. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat. Chem. Biol. 7:566–74 [Google Scholar]
  157. Zheng YC, Yu B, Jiang GZ, Feng XJ, He PX. 157.  et al. 2016. Irreversible LSD1 inhibitors: application of tranylcypromine and its derivatives in cancer treatment. Curr. Top. Med. Chem. 16:2179–88 [Google Scholar]
  158. Sugino N, Kawahara M, Tatsumi G, Kanai A, Matsui H. 158.  et al. 2017. A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers. Leukemia In press. https://doi.org/10.1038/leu.2017.59 [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010716-105106
Loading
/content/journals/10.1146/annurev-pharmtox-010716-105106
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