Vol 10, No 1 (2019)
Review paper
Published online: 2019-06-19

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EZH2 methyltransferase as a therapeutic target in hematological malignancies

Beata Pytlak1, Maria Chraszczewska1, Monika Prochorec-Sobieszek1, Anna Szumera-Ciećkiewicz
DOI: 10.5603/Hem.2019.0012
Hematologia 2019;10(1):9-18.

Abstract

EZH2 methyltransferase is the subunit of the PRC2 complex that catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3). EZH2 is one of the Polycomb proteins that are the main epigenetic factors and are responsible for silencing and inactivating genes. This enzyme has a dual function in cancer - it is an oncogene and a suppressor gene. Abnormalities resulting from overexpression or mutation in EZH2 coding genes have been found in patients suffering from hematological malignancies and solid cancers. Therefore, it is necessary to treat these patients, has begun studies on molecules directed against the PRC2 complex, in particular against EZH1/EZH2. In 2012, a breakthrough in the development of targeted therapy with inhibitors of methyltransferase EZH2 has been the discovery of highly selective compounds containing the 2-pyridine in their chemical structure. In this review, draws attention to the latest findings regarding the oncogenic functions of EZH2 methyltransferase and their impact on the development of tumors. In addition, the text contains current information about preclinical and clinical trials on EZH2 inhibitors testing mainly in hematological cancers.

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References

  1. Fioravanti R, Stazi G, Zwergel C, et al. Six Years (2012-2018) of Researches on Catalytic EZH2 Inhibitors: The Boom of the 2-Pyridone Compounds. Chem Rec. 2018; 18(12): 1818–1832.
  2. Wen Y, Cai J, Hou Y, et al. Role of EZH2 in cancer stem cells: from biological insight to a therapeutic target. Oncotarget. 2017; 8(23): 37974–37990.
  3. Gan Lu, Yang Y, Li Q, et al. Epigenetic regulation of cancer progression by EZH2: from biological insights to therapeutic potential. Biomark Res. 2018; 6: 10.
  4. Andricovich J, Kai Y, Peng W, et al. Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis. J Clin Invest. 2016; 126(3): 905–920.
  5. He A, Shen X, Ma Q, et al. PRC2 directly methylates GATA4 and represses its transcriptional activity. Genes Dev. 2012; 26(1): 37–42.
  6. Lee JiM, Lee JS, Kim H, et al. EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol Cell. 2012; 48(4): 572–586.
  7. Gunawan M, Venkatesan N, Loh JT, et al. The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin. Nat Immunol. 2015; 16(5): 505–516.
  8. Kim E, Kim M, Woo DH, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell. 2013; 23(6): 839–852.
  9. Lee ST, Li Z, Wu Z, et al. Context-specific regulation of NF-κB target gene expression by EZH2 in breast cancers. Mol Cell. 2011; 43(5): 798–810.
  10. Xu K, Wu ZJ, Groner AC, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012; 338(6113): 1465–1469.
  11. Jung HY, Jun S, Lee M, et al. PAF and EZH2 induce Wnt/β-catenin signaling hyperactivation. Mol Cell. 2013; 52(2): 193–205.
  12. Yan J, Ng SB, Tay JLS, et al. EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity. Blood. 2013; 121(22): 4512–4520.
  13. Zhang K, Zhang Y, Ren K, et al. MicroRNA-101 inhibits the metastasis of osteosarcoma cells by downregulation of EZH2 expression. Oncol Rep. 2014; 32(5): 2143–2149.
  14. Wang HJ, Ruan HJ, He XJ, et al. MicroRNA-101 is down-regulated in gastric cancer and involved in cell migration and invasion. Eur J Cancer. 2010; 46(12): 2295–2303.
  15. Varambally S, Cao Qi, Mani RS, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 2008; 322(5908): 1695–1699.
  16. Han Li C, Chen Y. Targeting EZH2 for cancer therapy: progress and perspective. Curr Protein Pept Sci. 2015; 16(6): 559–570.
  17. Varambally S, Dhanasekaran SM, Zhou M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002; 419(6907): 624–629.
  18. Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010; 42(2): 181–185.
  19. van Haaften G, Dalgliesh GL, Davies H, et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet. 2009; 41(5): 521–523.
  20. McCabe MT, Graves AP, Ganji G, 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 U S A. 2012; 109(8): 2989–2994.
  21. Kim KH, Roberts CWM. Targeting EZH2 in cancer. Nat Med. 2016; 22(2): 128–134.
  22. Yamagishi M, Uchimaru K. Targeting EZH2 in cancer therapy. Curr Opin Oncol. 2017; 29(5): 375–381.
  23. Majer CR, Jin L, Scott MP, et al. A687V EZH2 is a gain-of-function mutation found in lymphoma patients. FEBS Lett. 2012; 586(19): 3448–3451.
  24. Kadoch C, Hargreaves DC, Hodges C, et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 2013; 45(6): 592–601.
  25. Wilson BG, Wang Xi, Shen X, et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell. 2010; 18(4): 316–328.
  26. Dubois S, Mareschal S, Picquenot JM, et al. Immunohistochemical and genomic profiles of diffuse large B-cell lymphomas: implications for targeted EZH2 inhibitor therapy? Oncotarget. 2015; 6(18): 16712–16724.
  27. Bödör C, Grossmann V, Popov N, et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood. 2013; 122(18): 3165–3168.
  28. Huet S, Xerri L, Tesson B, et al. EZH2 alterations in follicular lymphoma: biological and clinical correlations. Blood Cancer J. 2017; 7(4): e555.
  29. Tian X, Pelton A, Shahsafaei A, et al. Differential expression of enhancer of zeste homolog 2 (EZH2) protein in small cell and aggressive B-cell non-Hodgkin lymphomas and differential regulation of EZH2 expression by p-ERK1/2 and MYC in aggressive B-cell lymphomas. Mod Pathol. 2016; 29(9): 1050–1057.
  30. Sashida G, Harada H, Matsui H, et al. Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation. Nat Commun. 2014; 5: 4177.
  31. Cabrero M, Wei Y, Yang H, et al. Down-regulation of EZH2 expression in myelodysplastic syndromes. Leuk Res. 2016; 44: 1–7.
  32. McGraw K, Nguyen J, Ali NAl, et al. Association of EZH2 protein expression by immunohistochemistry in myelodysplasia related neoplasms with mutation status, cytogenetics and clinical outcomes. Br J Haematol. 2018; 184(3): 450–455.
  33. Pawlyn C, Bright MD, Buros AF, et al. Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. Blood Cancer J. 2017; 7(3): e549.
  34. Chase A, Cross NCP. Aberrations of EZH2 in cancer. Clin Cancer Res. 2011; 17(9): 2613–2618.
  35. Pourakbar S, Pluard TJ, Accurso AD, et al. Ezh2, a novel target in detection and therapy of breast cancer. Onco Targets Ther. 2017; 10: 2685–2687.
  36. Chen Z, Yang P, Li W, et al. Expression of EZH2 is associated with poor outcome in colorectal cancer. Oncol Lett. 2018; 15(3): 2953–2961.
  37. Vilorio-Marqués L, Martín V, Diez-Tascón C, et al. The role of EZH2 in overall survival of colorectal cancer: a meta-analysis. Sci Rep. 2017; 7(1): 13806.
  38. Changchien YC, Tátrai P, Papp G, et al. Poorly differentiated synovial sarcoma is associated with high expression of enhancer of zeste homologue 2 (EZH2). J Transl Med. 2012; 10: 216.
  39. Tang SH, Huang HS, Wu HU, et al. Pharmacologic down-regulation of EZH2 suppresses bladder cancer in vitro and in vivo. Oncotarget. 2014; 5(21): 10342–10355.
  40. Jiang X, Lim CZ, Li Z, et al. Functional Characterization of D9, a Novel Deazaneplanocin A (DZNep) Analog, in Targeting Acute Myeloid Leukemia (AML). PLoS One. 2015; 10(4): e0122983.
  41. Knutson SK, Wigle TJ, Warholic NM, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012; 8(11): 890–896.
  42. Qi W, Chan H, Teng L, et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A. 2012; 109(52): 21360–21365.
  43. Konze KD, Ma A, Li F, et al. An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem Biol. 2013; 8(6): 1324–1334.
  44. Xu B, On DM, Ma A, et al. Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood. 2015; 125(2): 346–357.
  45. Grinshtein N, Rioseco CC, Marcellus R, et al. Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells. Oncotarget. 2016; 7(37): 59360–59376.
  46. Knutson SK, Warholic NM, Wigle TJ, et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013; 110(19): 7922–7927.
  47. Campbell JE, Kuntz KW, Knutson SK, et al. EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity. ACS Med Chem Lett. 2015; 6(5): 491–495.
  48. Song X, Gao T, Wang N, et al. Selective inhibition of EZH2 by ZLD1039 blocks H3K27 methylation and leads to potent anti-tumor activity in breast cancer. Sci Rep. 2016; 6: 20864.
  49. Lu B, Shen X, Zhang L, et al. Discovery of EBI-2511: A Highly Potent and Orally Active EZH2 Inhibitor for the Treatment of Non-Hodgkin's Lymphoma. ACS Med Chem Lett. 2018; 9(2): 98–102.
  50. Honma D, Kanno O, Watanabe J, et al. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci. 2017; 108(10): 2069–2078.
  51. Mellini P, Marrocco B, Borovika D, et al. Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells. Philos Trans R Soc Lond B Biol Sci. 2018; 373(1748).
  52. Miele E, Valente S, Alfano V, et al. The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells. Oncotarget. 2017; 8(40): 68557–68570.
  53. Bradley WD, Arora S, Busby J, et al. EZH2 inhibitor efficacy in non-Hodgkin's lymphoma does not require suppression of H3K27 monomethylation. Chem Biol. 2014; 21(11): 1463–1475.
  54. Gehling VS, Vaswani RG, Nasveschuk CG, et al. Discovery, design, and synthesis of indole-based EZH2 inhibitors. Bioorg Med Chem Lett. 2015; 25(17): 3644–3649.
  55. Vaswani RG, Gehling VS, Dakin LA, et al. Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas. J Med Chem. 2016; 59(21): 9928–9941.



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