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 EZH2 in cancer

Abstract

Recent genomic studies have resulted in an emerging understanding of the role of chromatin regulators in the development of cancer. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex, is recurrently mutated in several forms of cancer and is highly expressed in numerous others. Notably, both gain-of-function and loss-of-function mutations occur in cancers but are associated with distinct cancer types. Here we review the spectrum of EZH2-associated mutations, discuss the mechanisms underlying EZH2 function, and synthesize a unifying perspective that the promotion of cancer arises from disruption of the role of EZH2 as a master regulator of transcription. We further discuss EZH2 inhibitors that are now showing early signs of promise in clinical trials and also additional strategies to combat roles of EZH2 in cancer.

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: The PRC2 complex and its function in transcriptional regulation.
Figure 2: EZH2 as a therapeutic target in cancer.

Similar content being viewed by others

References

  1. Orkin, S.H. & Hochedlinger, K. Chromatin connections to pluripotency and cellular reprogramming. Cell 145, 835–850 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Creyghton, M.P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl. Acad. Sci. USA 107, 21931–21936 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mikkelsen, T.S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bernstein, B.E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Cui, K. et al. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell 4, 80–93 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470, 279–283 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Dalgliesh, G.L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gui, Y. et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat. Genet. 43, 875–878 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ho, A.S. et al. The mutational landscape of adenoid cystic carcinoma. Nat. Genet. 45, 791–798 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Huether, R. et al. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat. Commun. 5, 3630 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Masliah-Planchon, J., Bièche, I., Guinebretière, J.M., Bourdeaut, F. & Delattre, O. SWI/SNF chromatin remodeling and human malignancies. Annu. Rev. Pathol. 10, 145–171 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Margueron, R. & Reinberg, D. The Polycomb complex PRC2 and its mark in life. Nature 469, 343–349 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Di Croce, L. & Helin, K. Transcriptional regulation by Polycomb group proteins. Nat. Struct. Mol. Biol. 20, 1147–1155 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Müller, J. et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111, 197–208 (2002).

    Article  PubMed  Google Scholar 

  15. Czermin, B. et al. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111, 185–196 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Bracken, A.P. et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 22, 5323–5335 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bachmann, I.M. et al. 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, 268–273 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Sauvageau, M. & Sauvageau, G. Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell 7, 299–313 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Herrera-Merchan, A. et al. Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease. Nat. Commun. 3, 623 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Kleer, C.G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl. Acad. Sci. USA 100, 11606–11611 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bödör, C. et al. EZH2 Y641 mutations in follicular lymphoma. Leukemia 25, 726–729 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Yap, D.B. et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117, 2451–2459 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sneeringer, C.J. et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl. Acad. Sci. USA 107, 20980–20985 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  26. McCabe, M.T. et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc. Natl. Acad. Sci. USA 109, 2989–2994 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Majer, C.R. et al. A687V EZH2 is a gain-of-function mutation found in lymphoma patients. FEBS Lett. 586, 3448–3451 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Pugh, T.J. et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488, 106–110 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jones, D.T. et al. Dissecting the genomic complexity underlying medulloblastoma. Nature 488, 100–105 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Waddell, N. et al. Australian Pancreatic Cancer Genome Initiative. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521–523 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jankowska, A.M. et al. Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood 118, 3932–3941 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lewis, E.B. A gene complex controlling segmentation in Drosophila. Nature 276, 565–570 (1978).

    Article  CAS  PubMed  Google Scholar 

  34. Struhl, G. A gene product required for correct initiation of segmental determination in Drosophila. Nature 293, 36–41 (1981).

    Article  CAS  PubMed  Google Scholar 

  35. Schuettengruber, B. & Cavalli, G. Recruitment of polycomb group complexes and their role in the dynamic regulation of cell fate choice. Development 136, 3531–3542 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Francis, N.J., Saurin, A.J., Shao, Z. & Kingston, R.E. Reconstitution of a functional core polycomb repressive complex. Mol. Cell 8, 545–556 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Workman, J.L. & Kingston, R.E. Alteration of nucleosome structure as a mechanism of transcriptional regulation. Annu. Rev. Biochem. 67, 545–579 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Kadoch, C. et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet. 45, 592–601 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wilson, B.G. et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18, 316–328 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kia, S.K., Gorski, M.M., Giannakopoulos, S. & Verrijzer, C.P. SWI/SNF mediates polycomb eviction and epigenetic reprogramming of the INK4b-ARF-INK4a locus. Mol. Cell. Biol. 28, 3457–3464 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bitler, B.G. et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat. Med. 21, 231–238 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Fillmore, C.M. et al. EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors. Nature 520, 239–242 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim, K.H. et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21, 1491–1496 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Thornton, S.R., Butty, V.L., Levine, S.S. & Boyer, L.A. Polycomb Repressive Complex 2 regulates lineage fidelity during embryonic stem cell differentiation. PLoS One 9, e110498 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lee, T.I. et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125, 301–313 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Boyer, L.A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Ezhkova, E. et al. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell 136, 1122–1135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chang, C.J. et al. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-catenin signaling. Cancer Cell 19, 86–100 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Caretti, G., Di Padova, M., Micales, B., Lyons, G.E. & Sartorelli, V. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev. 18, 2627–2638 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang, L., Jin, Q., Lee, J.E., Su, I.H. & Ge, K. Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis. Proc. Natl. Acad. Sci. USA 107, 7317–7322 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Schwarz, D. et al. Ezh2 is required for neural crest-derived cartilage and bone formation. Development 141, 867–877 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Du, J. et al. FOXC1, a target of polycomb, inhibits metastasis of breast cancer cells. Breast Cancer Res. Treat. 131, 65–73 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. Cao, Q. et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 27, 7274–7284 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bruggeman, S.W. et al. Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev. 19, 1438–1443 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shi, B. et al. Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol. Cell. Biol. 27, 5105–5119 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jung, H.Y. et al. PAF and EZH2 induce Wnt/β-catenin signaling hyperactivation. Mol. Cell 52, 193–205 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lee, S.T. et al. Context-specific regulation of NF-κB target gene expression by EZH2 in breast cancers. Mol. Cell 43, 798–810 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Gonzalez, M.E. et al. EZH2 expands breast stem cells through activation of NOTCH1 signaling. Proc. Natl. Acad. Sci. USA 111, 3098–3103 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xu, K. et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 338, 1465–1469 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kim, E. et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23, 839–852 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Higa, L.A. et al. CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation. Nat. Cell Biol. 8, 1277–1283 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Lee, J.M. et al. EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol. Cell 48, 572–586 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Glazer, R.I. et al. 3-Deazaneplanocin: a new and potent inhibitor of S-adenosylhomocysteine hydrolase and its effects on human promyelocytic leukemia cell line HL-60. Biochem. Biophys. Res. Commun. 135, 688–694 (1986).

    Article  CAS  PubMed  Google Scholar 

  64. Tan, J. et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 21, 1050–1063 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Miranda, T.B. et al. DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol. Cancer Ther. 8, 1579–1588 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Knutson, S.K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8, 890–896 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Verma, S.K. et al. Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS Med. Chem. Lett. 3, 1091–1096 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  69. Qi, W. et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc. Natl. Acad. Sci. USA 109, 21360–21365 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Konze, K.D. et al. An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem. Biol. 8, 1324–1334 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Knutson, S.K. et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc. Natl. Acad. Sci. USA 110, 7922–7927 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Knutson, S.K. et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol. Cancer Ther. 13, 842–854 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Kim, W. et al. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat. Chem. Biol. 9, 643–650 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gibaja, V. et al. Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors. Oncogene (2015).

  75. Baude, A., Lindroth, A.M. & Plass, C. PRC2 loss amplifies Ras signaling in cancer. Nat. Genet. 46, 1154–1155 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. De Raedt, T. et al. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell 20, 400–413 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Knutson, S.K. et al. Synergistic anti-tumor activity of EZH2 inhibitors and glucocorticoid receptor agonists in models of germinal center non-Hodgkin lymphomas. PLoS One 9, e111840 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kirk, J.S. et al. Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer. Oncotarget 6, 3136–3146 (2015).

    Article  PubMed  Google Scholar 

  79. Sashida, G. et al. Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation. Nat. Commun. 5, 4177 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Ernst, T. et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat. Genet. 42, 722–726 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Nikoloski, G. et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat. Genet. 42, 665–667 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Ntziachristos, P. et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat. Med. 18, 298–301 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Simon, C. et al. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev. 26, 651–656 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lee, W. et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat. Genet. 46, 1227–1232 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Koontz, J.I. et al. Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc. Natl. Acad. Sci. USA 98, 6348–6353 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Li, H. et al. Effects of rearrangement and allelic exclusion of JJAZ1/SUZ12 on cell proliferation and survival. Proc. Natl. Acad. Sci. USA 104, 20001–20006 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Zhang, M. et al. Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat. Genet. 46, 1170–1172 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ueda, T. et al. EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms. Leukemia 26, 2557–2560 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Lessard, J. et al. Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation. Genes Dev. 13, 2691–2703 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Score, J. et al. Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms. Blood 119, 1208–1213 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Chen, H.W. et al. A novel infusible botanically-derived drug, PG2, for cancer-related fatigue: a phase II double-blind, randomized placebo-controlled study. Clin. Invest. Med. 35, E1–E11 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. 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).

    Article  CAS  PubMed  Google Scholar 

  95. Lewis, P.W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Fujii, S., Ito, K., Ito, Y. & Ochiai, A. Enhancer of zeste homologue 2 (EZH2) down-regulates RUNX3 by increasing histone H3 methylation. J. Biol. Chem. 283, 17324–17332 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yang, X. et al. CDKN1C (p57) is a direct target of EZH2 and suppressed by multiple epigenetic mechanisms in breast cancer cells. PLoS One 4, e5011 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ren, G. et al. Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Cancer Res. 72, 3091–3104 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Truax, A.D., Thakkar, M. & Greer, S.F. Dysregulated recruitment of the histone methyltransferase EZH2 to the class II transactivator (CIITA) promoter IV in breast cancer cells. PLoS One 7, e36013 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Taniguchi, H. et al. Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer. Oncogene 31, 1988–1994 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Chen, H., Tu, S.W. & Hsieh, J.T. Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer. J. Biol. Chem. 280, 22437–22444 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Beke, L., Nuytten, M., Van Eynde, A., Beullens, M. & Bollen, M. The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2. Oncogene 26, 4590–4595 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Chen, Y. et al. Proteomic analysis of EZH2 downstream target proteins in hepatocellular carcinoma. Proteomics 7, 3097–3104 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Yu, J. et al. The neuronal repellent SLIT2 is a target for repression by EZH2 in prostate cancer. Oncogene 29, 5370–5380 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Min, J. et al. An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-κB. Nat. Med. 16, 286–294 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Shin, Y.J. & Kim, J.H. The role of EZH2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cells. PLoS One 7, e30393 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Jia, N. et al. Enhancer of zeste homolog 2 is involved in the proliferation of endometrial carcinoma. Oncol. Lett. 8, 2049–2054 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Eskander, R.N. et al. Inhibition of enhancer of zeste homolog 2 (EZH2) expression is associated with decreased tumor cell proliferation, migration, and invasion in endometrial cancer cell lines. Int. J. Gynecol. Cancer 23, 997–1005 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Fan, T. et al. EZH2-dependent suppression of a cellular senescence phenotype in melanoma cells by inhibition of p21/CDKN1A expression. Mol. Cancer Res. 9, 418–429 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zingg, D. et al. The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors. Nat. Commun. 6, 6051 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. Weikert, S. et al. Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int. J. Mol. Med. 16, 349–353 (2005).

    CAS  PubMed  Google Scholar 

  112. Raman, J.D. et al. Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin. Cancer Res. 11, 8570–8576 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Lee, J. et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 13, 69–80 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sudo, T. et al. Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br. J. Cancer 92, 1754–1758 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hussain, M. et al. Tobacco smoke induces polycomb-mediated repression of Dickkopf-1 in lung cancer cells. Cancer Res. 69, 3570–3578 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Yan, J. et al. EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity. Blood 121, 4512–4520 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Lu, C. et al. Regulation of tumor angiogenesis by EZH2. Cancer Cell 18, 185–197 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Caganova, M. et al. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J. Clin. Invest. 123, 5009–5022 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Hayden, A., Johnson, P.W., Packham, G. & Crabb, S.J. S-adenosylhomocysteine hydrolase inhibition by 3-deazaneplanocin A analogues induces anti-cancer effects in breast cancer cell lines and synergy with both histone deacetylase and HER2 inhibition. Breast Cancer Res. Treat. 127, 109–119 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Kemp, C.D. et al. Polycomb repressor complex-2 is a novel target for mesothelioma therapy. Clin. Cancer. Res. 18, 77–90 (2012).

    Article  CAS  PubMed  Google Scholar 

  121. Suvà, M.L. et al. EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res. 69, 9211–9218 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Smits, M. et al. Down-regulation of miR-101 in endothelial cells promotes blood vessel formation through reduced repression of EZH2. PLoS One 6, e16282 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

K.H.K. was supported by an award from the National Cancer Center. C.W.M.R. was supported by US National Cancer Institute grants R01CA172152 and R01CA113794. The Garrett B. Smith Foundation, the Cure AT/RT Now foundation, The Avalanna Fund and Miles for Mary provided additional support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Charles W M Roberts.

Ethics declarations

Competing interests

As a recipient of a Dana-Farber Cancer Institute-Novartis Institutes for Biomedical Research Drug Discovery Program research grant, C.W.M.R. received research funding and consulting fees from the Novartis Institutes for Biomedical Research.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, K., Roberts, C. Targeting EZH2 in cancer. Nat Med 22, 128–134 (2016). https://doi.org/10.1038/nm.4036

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4036

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