1932

Abstract

The organization of the chromatin structure is essential for maintaining cell-type-specific gene expression and therefore for cell identity. This structure is highly dynamic and is regulated by a large number of chromatin-associated proteins that are required for normal development and differentiation. Recurrent somatic mutations have been found with high frequency in genes coding for chromatin-associated proteins in cancer, and several of these are required for cancer maintenance. In this review, we discuss recent advances in understanding the role of chromatin-associated proteins in transcription, development, and cancer. Specifically, we focus on selected examples of proteins belonging to the histone methyltransferase, histone demethylase, or bromodomain families, for which specific small molecule inhibitors have been developed and are in either preclinical or clinical trials.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-050216-034422
2017-03-06
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/1/1/annurev-cancerbio-050216-034422.html?itemId=/content/journals/10.1146/annurev-cancerbio-050216-034422&mimeType=html&fmt=ahah

Literature Cited

  1. Agger K, Cloos PA, Christensen J, Pasini D, Rose S. et al. 2007. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449:731–34 [Google Scholar]
  2. Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G. et al. 2009. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev 23:1171–76 [Google Scholar]
  3. Agger K, Miyagi S, Pedersen MT, Kooistra SM, Johansen JV, Helin K. 2016. Jmjd2/Kdm4 demethylases are required for expression of Il3ra and survival of acute myeloid leukemia cells. Genes Dev 30:1278–88 [Google Scholar]
  4. Alekseyenko AA, Walsh EM, Wang X, Grayson AR, Hsi PT. et al. 2015. The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains. Genes Dev 29:1507–23 [Google Scholar]
  5. Alinari L, Mahasenan KV, Yan F, Karkhanis V, Chung JH. et al. 2015. Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. Blood 125:2530–43 [Google Scholar]
  6. Andor N, Ihara Y, Lerner R, Gan H, Chen X. et al. 2014. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat. Med. 20:1394–96 [Google Scholar]
  7. Arcipowski KM, Martinez CA, Ntziachristos P. 2016. Histone demethylases in physiology and cancer: a tale of two enzymes, JMJD3 and UTX. Curr. Opin. Genet. Dev. 36:59–67 [Google Scholar]
  8. Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O. et al. 2006. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J. Clin. Oncol. 24:268–73 [Google Scholar]
  9. Barradas M, Anderton E, Acosta JC, Li S, Banito A. et al. 2009. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev 23:1177–82 [Google Scholar]
  10. Beguelin W, Popovic R, Teater M, Jiang Y, Bunting KL. et al. 2013. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23:677–92 [Google Scholar]
  11. Benito JM, Godfrey L, Kojima K, Hogdal L, Wunderlich M. et al. 2015. MLL-rearranged acute lymphoblastic leukemias activate BCL-2 through H3K79 methylation and are sensitive to the BCL-2-specific antagonist ABT-199. Cell Rep 13:2715–27 [Google Scholar]
  12. Benyoucef A, Palii CG, Wang C, Porter CJ, Chu A. et al. 2016. UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia. Genes Dev 30:508–21 [Google Scholar]
  13. Berg T, Thoene S, Yap D, Wee T, Schoeler N. et al. 2014. A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis. Blood 123:3914–24 [Google Scholar]
  14. Bernard A, Jin M, González-Rodríguez P, Füllgrabe J, Delorme-Axford E. et al. 2015. Rph1/KDM4 mediates nutrient-limitation signaling that leads to the transcriptional induction of autophagy. Curr. Biol. 25:546–55 [Google Scholar]
  15. Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J. et al. 2011. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20:66–78 [Google Scholar]
  16. Berry WL, Janknecht R. 2013. KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Cancer Res 73:2936–42 [Google Scholar]
  17. Beyer S, Kristensen MM, Jensen KS, Johansen JV, Staller P. 2008. The histone demethylases JMJD1A and JMJD2B are transcriptional targets of hypoxia-inducible factor HIF. J. Biol. Chem. 283:36542–52 [Google Scholar]
  18. Binda C, Valente S, Romanenghi M, Pilotto S, Cirilli R. et al. 2010. Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. J. Am. Chem. Soc. 132:6827–33 [Google Scholar]
  19. Black JC, Manning AL, Van Rechem C, Kim J, Ladd B. et al. 2013. KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell 154:541–55 [Google Scholar]
  20. Bodor C, O'Riain C, Wrench D, Matthews J, Iyengar S. et al. 2011. EZH2 Y641 mutations in follicular lymphoma. Leukemia 25:726–29 [Google Scholar]
  21. Bosselut R. 2016. Pleiotropic functions of H3K27Me3 demethylases in immune cell differentiation. Trends Immunol 37:102–13 [Google Scholar]
  22. Bossi D, Cicalese A, Dellino GI, Luzi L, Riva L. et al. 2016. In vivo genetic screens of patient-derived tumors revealed unexpected frailty of the transformed phenotype. Cancer Discov 6:650–63 [Google Scholar]
  23. Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K. 2003. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J 22:5323–35 [Google Scholar]
  24. Buenrostro JD, Wu B, Litzenburger UM, Ruff D, Gonzales ML. et al. 2015. Single-cell chromatin accessibility reveals principles of regulatory variation. Nature 523:486–90 [Google Scholar]
  25. Cao J, Liu Z, Cheung WKC, Zhao M, Chen SY. et al. 2014. Histone demethylase RBP2 is critical for breast cancer progression and metastasis. Cell Rep 6:868–77 [Google Scholar]
  26. Cejas P, Li L, O'Neill NK, Duarte M, Rao P. et al. 2016. Chromatin immunoprecipitation from fixed clinical tissues reveals tumor-specific enhancer profiles. Nat. Med. 22:685–91 [Google Scholar]
  27. Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ. 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]
  28. Chapuy B, McKeown MR, Lin CY, Monti S, Roemer MGM. et al. 2013. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell 24:777–90 [Google Scholar]
  29. Chari A, Golas MM, Klingenhager M, Neuenkirchen N, Sander B. et al. 2008. An assembly chaperone collaborates with the SMN complex to generate spliceosomal SnRNPs. Cell 135:497–509 [Google Scholar]
  30. Chen CW, Armstrong SA. 2015. Targeting DOT1L and HOX gene expression in. MLL -rearranged leukemia and beyond. Exp. Hematol 43:673–84 [Google Scholar]
  31. Chen CW, Koche RP, Sinha AU, Deshpande AJ, Zhu N. et al. 2015. DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia. Nat. Med. 21:335–43 [Google Scholar]
  32. Cheung N, Fung TK, Zeisig BB, Holmes K, Rane JK. et al. 2016. Targeting aberrant epigenetic networks mediated by PRMT1 and KDM4C in acute myeloid leukemia. Cancer Cell 29:32–48 [Google Scholar]
  33. Chin Y-W, Han S-Y. 2015. KDM4 histone demethylase inhibitors for anti-cancer agents: a patent review. Expert Opin. Ther. Patents 25:135–44 [Google Scholar]
  34. Cloos PAC, Christensen J, Agger K, Maiolica A, Rappsilber J. et al. 2006. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442:307–11 [Google Scholar]
  35. Copeland RA, Moyer MP, Richon VM. 2013. Targeting genetic alterations in protein methyltransferases for personalized cancer therapeutics. Oncogene 32:939–46 [Google Scholar]
  36. Cromer MK, Starker LF, Choi M, Udelsman R, Nelson-Williams C. et al. 2012. Identification of somatic mutations in parathyroid tumors using whole-exome sequencing. J. Clin. Endocrinol. Metab. 97:E1774–81 [Google Scholar]
  37. Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L. et al. 2013. Potent inhibition of DOT1L as treatment for MLL-fusion leukemia. Blood 122:2533–41 [Google Scholar]
  38. Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ. et al. 2011. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20:53–65 [Google Scholar]
  39. Das PP, Shao Z, Beyaz S, Apostolou E, Pinello L. et al. 2014. Distinct and combinatorial functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in mouse embryonic stem cell identity. Mol. Cell 53:32–48 [Google Scholar]
  40. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M. et al. 2011. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478:529–33 [Google Scholar]
  41. De Raedt T, Beert E, Pasmant E, Luscan A, Brems H. et al. 2014. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 514:247–51 [Google Scholar]
  42. De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G. 2007. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130:1083–94 [Google Scholar]
  43. de Vries NA, Hulsman D, Akhtar W, de Jong J, Miles DC. et al. 2015. Prolonged Ezh2 depletion in glioblastoma causes a robust switch in cell fate resulting in tumor progression. Cell Rep 10:383–97 [Google Scholar]
  44. Di Croce L, Helin K. 2013. Transcriptional regulation by Polycomb group proteins. Nat. Struct. Mol. Biol. 20:1147–55 [Google Scholar]
  45. Ernst J, Ernst J, Kellis M, Kellis M. 2010. Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat. Biotechnol. 28:817–25 [Google Scholar]
  46. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C. et al. 2010. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat. Genet. 42:722–26 [Google Scholar]
  47. Fanelli M, Amatori S, Barozzi I, Minucci S. 2011. Chromatin immunoprecipitation and high-throughput sequencing from paraffin-embedded pathology tissue. Nat. Protoc. 6:1905–19 [Google Scholar]
  48. Feng Y, Yang Y, Ortega MM, Copeland JN, Zhang M. et al. 2010. Early mammalian erythropoiesis requires the Dot1L methyltransferase. Blood 116:4483–91 [Google Scholar]
  49. Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SGT. et al. 2014. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia 28:2155–64 [Google Scholar]
  50. Fong CY, Gilan O, Lam EYN, Rubin AF, Ftouni S. et al. 2015. BET inhibitor resistance emerges from leukaemia stem cells. Nature 525:538–42 [Google Scholar]
  51. French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. 2003. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res 63:304–7 [Google Scholar]
  52. Grayson AR, Walsh EM, Cameron MJ, Godec J, Ashworth T. et al. 2014. MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma. Oncogene 33:1736–42 [Google Scholar]
  53. Hamamoto R, Saloura V, Nakamura Y. 2015. Critical roles of non-histone protein lysine methylation in human tumorigenesis. Nat. Rev. Cancer 15:110–24 [Google Scholar]
  54. Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR. et al. 2012. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21:473–87 [Google Scholar]
  55. Heinemann B, Nielsen JM, Hudlebusch HR, Lees MJ, Larsen DV. et al. 2014. Inhibition of demethylases by GSK-J1/J4. Nature 514:E1–2 [Google Scholar]
  56. Helin K, Dhanak D. 2013. Chromatin proteins and modifications as drug targets. Nature 502:480–88 [Google Scholar]
  57. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M. et al. 2012. A landscape of driver mutations in melanoma. Cell 150:251–63 [Google Scholar]
  58. Højfeldt JW, Agger K, Helin K. 2013. Histone lysine demethylases as targets for anticancer therapy. Nat. Rev. Drug Discov. 12:917–30 [Google Scholar]
  59. Issa JP, Kantarjian HM. 2009. Targeting DNA methylation. Clin. Cancer Res. 15:3938–46 [Google Scholar]
  60. Jin W, Tang Q, Wan M, Cui K, Zhang Y. et al. 2015. Genome-wide detection of DNase I hypersensitive sites in single cells and FFPE tissue samples. Nature 528:142–46 [Google Scholar]
  61. Jones B, Su H, Bhat A, Lei H, Bajko J. et al. 2008. The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure. PLOS Genet 4:e1000190 [Google Scholar]
  62. Khan O, La Thangue NB. 2012. HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol. Cell Biol. 90:85–94 [Google Scholar]
  63. Kim KH, Kim W, Howard TP, Vazquez F, Tsherniak A. et al. 2015. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21:1491–96 [Google Scholar]
  64. Klaus CR, Iwanowicz D, Johnston D, Campbell CA, Smith JJ. et al. 2014. DOT1L inhibitor EPZ-5676 displays synergistic antiproliferative activity in combination with standard of care drugs and hypomethylating agents in MLL-rearranged leukemia cells. J. Pharmacol. Exp. Ther. 350:646–56 [Google Scholar]
  65. Kleer CG, Cao Q, Varambally S, Shen R, Ota I. 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]
  66. Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG. et al. 2014. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat. Genet. 46:364–70 [Google Scholar]
  67. Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ. et al. 2013. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. PNAS 110:7922–27 [Google Scholar]
  68. Koh CM, Bezzi M, Low DH, Ang WX, Teo SX. et al. 2015. MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature 523:96–100 [Google Scholar]
  69. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A. et al. 2012. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat. Genet. 44:1006–14 [Google Scholar]
  70. Kruidenier L, Chung C-W, Cheng Z, Liddle J, Che K. et al. 2012. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488:404–8 [Google Scholar]
  71. Kryukov GV, Wilson FH, Ruth JR, Paulk J, Tsherniak A. et al. 2016. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351:1214–18 [Google Scholar]
  72. Kuntimaddi A, Achille NJ, Thorpe J, Lokken AA, Singh R. et al. 2015. Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 di- and tri-methylation on target genes and transformation potential. Cell Rep 11:808–20 [Google Scholar]
  73. Laugesen A, Helin K. 2014. Chromatin repressive complexes in stem cells, development, and cancer. Cell Stem Cell 14:735–51 [Google Scholar]
  74. Laugesen A, Højfeldt J, Helin K. 2016. Role of the polycomb repressive complex 2 (PRC2) in transcriptional regulation and cancer. Cold Spring Harb. Perspect. Med. In press
  75. Laurent B, Ruitu L, Murn J, Hempel K, Ferrao R. et al. 2015. A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation. Mol. Cell 57:957–70 [Google Scholar]
  76. Lee MG, Villa R, Trojer P, Norman J, Yan K-P. et al. 2007. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318:447–50 [Google Scholar]
  77. Lee MG, Wynder C, Schmidt DM, McCafferty DG, Shiekhattar R. 2006. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem. Biol. 13:563–67 [Google Scholar]
  78. Lee W, Teckie S, Wiesner T, Ran L, Prieto Granada CN. et al. 2014. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat. Genet. 46:1227–32 [Google Scholar]
  79. Lewis EB. 1978. A gene complex controlling segmentation in Drosophila. Nature 276:565–70 [Google Scholar]
  80. Lewis PH. 1947. New mutants report. Drosoph. Inf. Serv. 21:69 [Google Scholar]
  81. Li Y, Chitnis N, Nakagawa H, Kita Y, Natsugoe S. et al. 2015. PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers. Cancer Discov 5:288–303 [Google Scholar]
  82. Li Z, Yu J, Hosohama L, Nee K, Gkountela S. et al. 2015. The Sm protein methyltransferase PRMT5 is not required for primordial germ cell specification in mice. EMBO J 34:748–58 [Google Scholar]
  83. Lin W, Cao J, Liu J, Beshiri ML, Fujiwara Y. et al. 2011. Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. PNAS 108:13379–86 [Google Scholar]
  84. Liu F, Cheng G, Hamard PJ, Greenblatt S, Wang L. et al. 2015. Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis. J. Clin. Invest. 125:3532–44 [Google Scholar]
  85. Liu G, Bollig-Fischer A, Kreike B, van de Vijver MJ, Abrams J. et al. 2009. Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene 28:4491–500 [Google Scholar]
  86. Luo W, Chang R, Zhong J, Pandey A, Semenza GL. 2012. Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression. PNAS 109:E3367–76 [Google Scholar]
  87. Maio M, Covre A, Fratta E, Di Giacomo AM, Taverna P. et al. 2015. Molecular pathways: at the crossroads of cancer epigenetics and immunotherapy. Clin. Cancer Res. 21:4040–47 [Google Scholar]
  88. Mavrakis KJ, McDonald ER 3rd, Schlabach MR, Billy E, Hoffman GR. et al. 2016. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351:1208–13 [Google Scholar]
  89. McCabe MT, Graves AP, Ganji G, Diaz E, Halsey WS. et al. 2012. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). PNAS 109:2989–94 [Google Scholar]
  90. McGrath JP, Williamson KE, Balasubramanian S, Odate S, Arora S. et al. 2016. Pharmacological inhibition of the histone lysine demethylase KDM1A suppresses the growth of multiple acute myeloid leukemia subtypes. Cancer Res 76:1975–88 [Google Scholar]
  91. Mendenhall EM, Williamson KE, Reyon D, Zou JY, Ram O. et al. 2013. Locus-specific editing of histone modifications at endogenous enhancers. Nat. Biotechnol. 31:1133–36 [Google Scholar]
  92. Metzger E, Wissmann M, Yin N, Muller JM, Schneider R. et al. 2005. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437:436–39 [Google Scholar]
  93. Mohammad HP, Smitheman KN, Kamat CD, Soong D, Federowicz KE. et al. 2015. A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC. Cancer Cell 28:57–69 [Google Scholar]
  94. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J. 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]
  95. Mosammaparast N, Kim H, Laurent B, Zhao Y, Lim HJ. et al. 2013. The histone demethylase LSD1/KDM1A promotes the DNA damage response. J. Cell Biol. 203:457–70 [Google Scholar]
  96. Nguyen AT, Taranova O, He J, Zhang Y. 2011. DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. Blood 117:6912–22 [Google Scholar]
  97. Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M. et al. 2010. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat. Genet. 42:665–67 [Google Scholar]
  98. Noberini R, Uggetti A, Pruneri G, Minucci S, Bonaldi T. 2016. Pathology tissue-quantitative mass spectrometry analysis to profile histone post-translational modification patterns in patient samples. Mol. Cell. Proteom. 15:866–77 [Google Scholar]
  99. Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T. et al. 2012. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat. Med. 18:298–301 [Google Scholar]
  100. Ntziachristos P, Tsirigos A, Welstead GG, Trimarchi T, Bakogianni S. et al. 2014. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514:513–17 [Google Scholar]
  101. O'Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T. 2001. The Polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol. 21:4330–36 [Google Scholar]
  102. Orzan F, Pellegatta S, Poliani PL, Pisati F, Caldera V. et al. 2011. Enhancer of Zeste 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells. Neuropathol. Appl. Neurobiol. 37:381–94 [Google Scholar]
  103. Park W-Y, Hong B-J, Lee J, Choi C, Kim M-Y. 2016. H3K27 demethylase JMJD3 employs the NF-κB and BMP signaling pathways to modulate the tumor microenvironment and promote melanoma progression and metastasis. Cancer Res 76:161–70 [Google Scholar]
  104. Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K. 2004. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 23:4061–71 [Google Scholar]
  105. Pedersen MT, Kooistra SM, Radzisheuskaya A, Laugesen A, Johansen JV. et al. 2016. Continual removal of H3K9 promoter methylation by Jmjd2 demethylases is vital for ESC self-renewal and early development. EMBO J 35:1550–64 [Google Scholar]
  106. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S. et al. 2015. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527:249–53 [Google Scholar]
  107. Pengelly AR, Copur O, Jackle H, Herzig A, Muller J. 2013. A histone mutant reproduces the phenotype caused by loss of histone-modifying factor Polycomb. Science 339:698–99 [Google Scholar]
  108. Porro A, Feuerhahn S, Lingner J. 2014. TERRA-reinforced association of LSD1 with MRE11 promotes processing of uncapped telomeres. Cell Rep 6:765–76 [Google Scholar]
  109. Rasmussen PB, Staller P. 2014. The KDM5 family of histone demethylases as targets in oncology drug discovery. Epigenomics 6:277–86 [Google Scholar]
  110. Rathert P, Roth M, Neumann T, Muerdter F, Roe J-S. et al. 2015. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature 525:543–47 [Google Scholar]
  111. Ribrag V, Soria JC, Michot J-M, Schmitt A, Postel-Vinay S. et al. 2015a. Phase 1 study of tazemetostat (EPZ-6438), an inhibitor of enhancer of zeste-homolog 2 (EZH2): preliminary safety and activity in relapsed or refractory non-Hodgkin lymphoma (NHL) patients Presented at Am. Soc. Hematol. Annu. Meet., 57th, Abstr 473
  112. Ribrag V, Soria JC, Reyderman L, Chen R, Salazar P. et al. 2015b. Phase 1 first-in-human study of the enhancer of zeste-homolog 2 (EZH2) histone methyl transferase inhibitor E7438. Ann. Oncol. 26:Suppl. 2ii10–11 [Google Scholar]
  113. Riising EM, Comet I, Leblanc B, Wu X, Johansen JV, Helin K. 2014. Gene silencing triggers polycomb repressive complex 2 recruitment to CpG islands genome wide. Mol. Cell 55:347–60 [Google Scholar]
  114. Roesch A, Fukunaga-Kalabis M, Schmidt EC, Zabierowski SE, Brafford PA. et al. 2010. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141:583–94 [Google Scholar]
  115. Roesch A, Vultur A, Bogeski I, Wang H, Zimmermann KM. et al. 2013. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh cells. Cancer Cell 23:811–25 [Google Scholar]
  116. Sashida G, Harada H, Matsui H, Oshima M, Yui M. et al. 2014. Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation. Nat. Commun. 5:4177 [Google Scholar]
  117. Schenk T, Chen WC, Göllner S, Howell L, Jin L. et al. 2012. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 18:605–11 [Google Scholar]
  118. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F. et al. 2010. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141:69–80 [Google Scholar]
  119. Shi J, Vakoc CR. 2014. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol. Cell 54:728–36 [Google Scholar]
  120. Shu S, Lin CY, He HH, Witwicki RM, Tabassum DP. et al. 2016. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529:413–17 [Google Scholar]
  121. Shumacher A, Faust C, Magnuson T. 1996. Positional cloning of a global regulator of anterior-posterior patterning in mice. Nature 383:250–53 [Google Scholar]
  122. Simon C, Chagraoui J, Krosl J, Gendron P, Wilhelm B. et al. 2012. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev 26:651–56 [Google Scholar]
  123. Smil D, Eram MS, Li F, Kennedy S, Szewczyk MM. et al. 2015. Discovery of a dual PRMT5-PRMT7 inhibitor. ACS Med. Chem. Lett. 6:408–12 [Google Scholar]
  124. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM. et al. 2010. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. PNAS 107:20980–85 [Google Scholar]
  125. Souroullas GP, Jeck WR, Parker JS, Simon JM, Liu JY. et al. 2016. An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat. Med. 22:632–40 [Google Scholar]
  126. Stathis A, Zucca E, Bekradda M, Gomez-Roca C, Delord J-P. et al. 2016. Clinical response of carcinomas harboring the BRD4-NUT oncoprotein to the targeted bromodomain inhibitor OTX015/MK-8628. Cancer Discov 6:492–500 [Google Scholar]
  127. Stazi G, Zwergel C, Valente S, Mai A. 2016. LSD1 inhibitors: a patent review (2010–2015). Expert Opin. Ther. Patents 26:565–80 [Google Scholar]
  128. Steger DJ, Lefterova MI, Ying L, Stonestrom AJ, Schupp M. et al. 2008. DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. Mol. Cell. Biol. 28:2825–39 [Google Scholar]
  129. Stein EM, Garcia-Manero G, Rizzieri DA, Tibes R, Berdeja JG. et al. 2015. A phase 1 study of the DOT1L inhibitor, pinometostat (EPZ-5676), in adults with relapsed or refractory leukemia: safety, clinical activity, exposure and target inhibition Presented at Am. Soc. Hematol. Annu. Meet., 57th, Abstr 2547
  130. Stein EM, Tallman MS. 2015. Mixed lineage rearranged leukaemia: pathogenesis and targeting DOT1L. Curr. Opin. Hematol. 22:92–96 [Google Scholar]
  131. Stopa N, Krebs JE, Shechter D. 2015. The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond. Cell. Mol. Life Sci. 72:2041–59 [Google Scholar]
  132. Stratikopoulos EE, Dendy M, Szabolcs M, Khaykin AJ, Lefebvre C. et al. 2015. Kinase and BET inhibitors together clamp inhibition of PI3K signaling and overcome resistance to therapy. Cancer Cell 27:837–51 [Google Scholar]
  133. Suvà ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H. et al. 2014. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 157:580–94 [Google Scholar]
  134. Tarighat SS, Santhanam R, Frankhouser D, Radomska HS, Lai H. 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]
  135. Tee WW, Pardo M, Theunissen TW, Yu L, Choudhary JS. et al. 2010. Prmt5 is essential for early mouse development and acts in the cytoplasm to maintain ES cell pluripotency. Genes Dev 24:2772–77 [Google Scholar]
  136. Tie F, Banerjee R, Conrad PA, Scacheri PC, Harte PJ. 2012. Histone demethylase UTX and chromatin remodeler BRM bind directly to CBP and modulate acetylation of histone H3 lysine 27. Mol. Cell. Biol. 32:2323–34 [Google Scholar]
  137. Upadhyay G, Chowdhury AH, Vaidyanathan B, Kim D, Saleque S. 2014. Antagonistic actions of Rcor proteins regulate LSD1 activity and cellular differentiation. PNAS 111:8071–76 [Google Scholar]
  138. Van De Wetering M, Francies HE, Francis JM, Bounova G, Iorio F. et al. 2015. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161:933–45 [Google Scholar]
  139. Vandamme J, Lettier G, Sidoli S, Di Schiavi E, Nørregaard Jensen O, Salcini AE. 2012. The C. elegans H3K27 demethylase UTX-1 is essential for normal development, independent of its enzymatic activity. PLOS Genet 8:e1002647 [Google Scholar]
  140. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C. et al. 2002. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419:624–29 [Google Scholar]
  141. Vlaming H, van Leeuwen F. 2016. The upstreams and downstreams of H3K79 methylation by DOT1L. Chromosoma In press
  142. Wada T, Koyama D, Kikuchi J, Honda H, Furukawa Y. 2015. Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation. Blood 125:3731–46 [Google Scholar]
  143. Wagner JM, Hackanson B, Lubbert M, Jung M. 2010. Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin. Epigenet. 1:117–36 [Google Scholar]
  144. Wang GG, Song J, Wang Z, Dormann HL, Casadio F. et al. 2009. Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 459:847–51 [Google Scholar]
  145. Wang J, Telese F, Tan Y, Li W, Jin C. et al. 2015. LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control. Nat. Neurosci. 18:1256–64 [Google Scholar]
  146. Wang R, Liu W, Helfer CM, Bradner JE, Hornick JL. et al. 2014. Activation of SOX2 expression by BRD4-NUT oncogenic fusion drives neoplastic transformation in NUT midline carcinoma. Cancer Res 74:3332–43 [Google Scholar]
  147. Watson IR, Takahashi K, Futreal PA, Chin L. 2013. Emerging patterns of somatic mutations in cancer. Nat. Rev. Genet. 14:703–18 [Google Scholar]
  148. Weikert S, Christoph F, Kollermann J, Muller M, Schrader M. et al. 2005. Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int. J. Mol. Med. 16:349–53 [Google Scholar]
  149. Whyte WA, Bilodeau S, Orlando DA, Hoke HA, Frampton GM. et al. 2012. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482:221–25 [Google Scholar]
  150. Williams K, Christensen J, Rappsilber J, Nielsen AL, Johansen JV, Helin K. 2014. The histone lysine demethylase JMJD3/KDM6B is recruited to p53 bound promoters and enhancer elements in a p53 dependent manner. PLOS ONE 9:e96545 [Google Scholar]
  151. Wilson BG, Wang X, Shen X, McKenna ES, Lemieux ME. et al. 2010. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18:316–28 [Google Scholar]
  152. Wong SHK, Goode DL, Iwasaki M, Wei MC, Kuo H-P. et al. 2015. The H3K4-methyl epigenome regulates leukemia stem cell oncogenic potential. Cancer Cell 28:198–209 [Google Scholar]
  153. Wouters BJ, Delwel R. 2016. Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood 127:42–52 [Google Scholar]
  154. Wyce A, Ganji G, Smitheman KN, Chung C-W, Korenchuk S. et al. 2013. BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models. PLOS ONE 8:e72967 [Google Scholar]
  155. Yamamoto S, Wu Z, Russnes HG, Takagi S, Peluffo G. et al. 2014. JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell 25:762–77 [Google Scholar]
  156. Yan F, Alinari L, Lustberg ME, Martin LK, Cordero-Nieves HM. et al. 2014. Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma. Cancer Res 74:1752–65 [Google Scholar]
  157. Yang J, Jubb AM, Pike L, Buffa FM, Turley H. et al. 2010. The histone demethylase JMJD2B is regulated by estrogen receptor and hypoxia, and is a key mediator of estrogen induced growth. Cancer Res 70:6456–66 [Google Scholar]
  158. Yang X, Lay F, Han H, Jones PA. 2010. Targeting DNA methylation for epigenetic therapy. Trends Pharmacol. Sci. 31:536–46 [Google Scholar]
  159. Yang Y, Bedford MT. 2013. Protein arginine methyltransferases and cancer. Nat. Rev. Cancer 13:37–50 [Google Scholar]
  160. Yang Y, Yin X, Yang H, Xu Y. 2015. Histone demethylase LSD2 acts as an E3 ubiquitin ligase and inhibits cancer cell growth through promoting proteasomal degradation of OGT. Mol. Cell 58:47–59 [Google Scholar]
  161. Yatim A, Benne C, Sobhian B, Laurent-Chabalier S, Deas O. et al. 2012. NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. Mol. Cell 48:445–58 [Google Scholar]
  162. Yu BD, Hess JL, Horning SE, Brown GA, Korsmeyer SJ. 1995. Altered Hox expression and segmental identity in Mll-mutant mice. Nature 378:505–8 [Google Scholar]
  163. Yu W, Chory EJ, Wernimont AK, Tempel W, Scopton A. et al. 2012. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat. Commun. 3:1288 [Google Scholar]
  164. Zhang T, Gunther S, Looso M, Kunne C, Kruger M. et al. 2015. Prmt5 is a regulator of muscle stem cell expansion in adult mice. Nat. Commun. 6:7140 [Google Scholar]
  165. Zhao DY, Gish G, Braunschweig U, Li Y, Ni Z. et al. 2016. SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination. Nature 529:48–53 [Google Scholar]
  166. Zhao L, Zhang Y, Gao Y, Geng P, Lu Y. et al. 2015. JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein. Cell Death Diff 22:1630–40 [Google Scholar]
  167. Zibetti C, Adamo A, Binda C, Forneris F, Toffolo E. et al. 2010. Alternative splicing of the histone demethylase LSD1/KDM1 contributes to the modulation of neurite morphogenesis in the mammalian nervous system. J. Neurosci. 30:2521–32 [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-050216-034422
Loading
/content/journals/10.1146/annurev-cancerbio-050216-034422
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