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Genetic Impairments of PRC2 Activity in Oncology: Problems and Prospects

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Abstract

PRC2 (Polycomb repressive complex 2) is a conserved protein complex in multicellular organisms that is required to maintain gene repression. The catalytic subunit of PRC2, the EZH2 protein, provides the methylation of histone H3K27 (H3K27me1/2/3). It was demonstrated that a number of human cancers were associated with overexpression of PRC2 subunits, as well as with mutations that enhanced the EZH2 catalytic activity. At the same time, a group of cancers correlate with mutations that inhibit PRC2. A number of small molecule inhibitors to the PRC2 subunits have been developed, primarily to EZH2. One of these, tazemetostat, received approval in January 2020 in the United States for the treatment of epithelioid sarcoma. This review focuses on the role of PRC2 in cancer development and summarizes information on the designed PRC2 inhibitors.

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REFERENCES

  1. Bracken, A.P., Brien, G.L., and Verrijzer, C.P., Dangerous liaisons: interplay between SWI/SNF, NuRD, and Polycomb in chromatin regulation and cancer, Genes Dev., 2019, vol. 33, nos. 15—16, pp. 936—959. https://doi.org/10.1101/gad.326066.119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Grossniklaus, U. and Paro, R., Transcriptional silencing by polycomb-group proteins, Cold Spring Harb. Perspect. Biol., 2014, vol. 6, no. 11. a019331. https://doi.org/10.1101/cshperspect.a019331

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kuroda, M.I., Kang, H., De, S., and Kassis, J.A., Dynamic competition of polycomb and trithorax in transcriptional programming, Annu. Rev. Biochem., 2020, vol. 89, pp. 235—253. https://doi.org/10.1146/annurev-biochem-120219-103641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Piunti, A. and Shilatifard, A., Epigenetic balance of gene expression by Polycomb and COMPASS families, Science, 2016, vol. 352, no. 6290. aad9780. https://doi.org/10.1126/science.aad9780

    Article  CAS  PubMed  Google Scholar 

  5. Schuettengruber, B., Bourbon, H.M., Di Croce, L., and Cavalli, G., Genome regulation by polycomb and trithorax: 70 years and counting, Cell, 2017, vol. 171, no. 1, pp. 34—57. https://doi.org/10.1016/j.cell.2017.08.002

    Article  CAS  PubMed  Google Scholar 

  6. Chetverina, D.A., Elizar’ev, P.V., Lomaev, D.V., et al., Control of the gene activity by polycomb and trithorax group proteins in Drosophila, Genetika, 2017, vol. 53, no. 2, pp. 133—154.

    CAS  PubMed  Google Scholar 

  7. Erokhin, M., Georgiev, P., and Chetverina, D., Drosophila DNA-binding proteins in polycomb repression, Epigenomes, 2018, vol. 2, no. 1, p. 1. https://doi.org/10.3390/epigenomes2010001

    Article  CAS  Google Scholar 

  8. Kassis, J.A., Kennison, J.A., and Tamkun, J.W., Polycomb and trithorax group genes in Drosophila, Genetics, 2017, vol. 206, no. 4, pp. 1699—1725. https://doi.org/10.1534/genetics.115.185116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mozgova, I. and Hennig, L., The polycomb group protein regulatory network, Annu. Rev. Plant Biol., 2015, vol. 66, pp. 269—296. https://doi.org/10.1146/annurev-arplant-043014-115627

    Article  CAS  PubMed  Google Scholar 

  10. Deevy, O. and Bracken, A.P., PRC2 functions in development and congenital disorders, Development, 2019, vol. 146, no. 19. https://doi.org/10.1242/dev.181354

  11. Kouznetsova, V.L., Tchekanov, A., Li, X., et al., Polycomb repressive 2 complex—molecular mechanisms of function, Protein Sci., 2019, vol. 28, no. 8, pp. 1387—1399. https://doi.org/10.1002/pro.3647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yu, J.R., Lee, C.H., Oksuz, O., et al., PRC2 is high maintenance, Genes Dev., 2019, vol. 33, nos. 15—16, pp. 903—935. https://doi.org/10.1101/gad.325050.119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Czermin, B., Melfi, R., McCabe, D., et al., Drosophila enhancer of zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites, Cell, 2002, vol. 111, no. 2, pp. 185—196.

    Article  CAS  PubMed  Google Scholar 

  14. Muller, J., Hart, C.M., Francis, N.J., et al., Histone methyltransferase activity of a Drosophila Polycomb group repressor complex, Cell, 2002, vol. 111, no. 2, pp. 197—208.

    Article  CAS  PubMed  Google Scholar 

  15. Cao, R., Wang, L., Wang, H., et al., Role of histone H3 lysine 27 methylation in Polycomb-group silencing, Science, 2002, vol. 298, no. 5595, pp. 1039—1043. https://doi.org/10.1126/science.1076997

    Article  CAS  PubMed  Google Scholar 

  16. Ferrari, K.J., Scelfo, A., Jammula, S., et al., Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity, Mol. Cell, 2014, vol. 53, no. 1, pp. 49—62. https://doi.org/10.1016/j.molcel.2013.10.030

    Article  CAS  PubMed  Google Scholar 

  17. Kuzmichev, A., Nishioka, K., Erdjument-Bromage, H., et al., Histone methyltransferase activity associated with a human multiprotein complex containing the enhancer of zeste protein, Genes Dev., 2002, vol. 16, no. 22, pp. 2893—2905. https://doi.org/10.1101/gad.1035902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cao, R. and Zhang, Y., SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex, Mol. Cell, 2004, vol. 15, no. 1, pp. 57—67. https://doi.org/10.1016/j.molcel.2004.06.020

    Article  CAS  PubMed  Google Scholar 

  19. Montgomery, N.D., Yee, D., Chen, A., et al., The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation, Curr. Biol., 2005, vol. 15, no. 10, pp. 942—947. https://doi.org/10.1016/j.cub.2005.04.051

    Article  CAS  PubMed  Google Scholar 

  20. Pasini, D., Bracken, A.P., Jensen, M.R., et al., Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity, EMBO J., 2004, vol. 23, no. 20, pp. 4061—4071. https://doi.org/10.1038/sj.emboj.7600402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Margueron, R., Justin, N., Ohno, K., et al., Role of the polycomb protein EED in the propagation of repressive histone marks, Nature, 2009, vol. 461, no. 7265, pp. 762—767. https://doi.org/10.1038/nature08398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Faust, C., Schumacher, A., Holdener, B., and Magnuson, T., The eed mutation disrupts anterior mesoderm production in mice, Development, 1995, vol. 121, no. 2, pp. 273—285.

    CAS  PubMed  Google Scholar 

  23. O’Carroll, D., Erhardt, S., Pagani, M., et al., The polycomb-group gene Ezh2 is required for early mouse development, Mol. Cell Biol., 2001, vol. 21, no. 13, pp. 4330—4336. https://doi.org/10.1128/MCB.21.13.4330-4336.2001

    Article  PubMed  PubMed Central  Google Scholar 

  24. Margueron, R., Li, G., Sarma, K., et al., Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms, Mol. Cell, 2008, vol. 32, no. 4, pp. 503—518. https://doi.org/10.1016/j.molcel.2008.11.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ezhkova, E., Lien, W.H., Stokes, N., et al., EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair, Genes Dev., 2011, vol. 25, no. 5, pp. 485—498. https://doi.org/10.1101/gad.2019811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Son, J., Shen, S.S., Margueron, R., and Reinberg, D., Nucleosome-binding activities within JARID2 and EZH1 regulate the function of PRC2 on chromatin, Genes Dev., 2013, vol. 27, no. 24, pp. 2663—2677. https://doi.org/10.1101/gad.225888.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shen, X., Liu, Y., Hsu, Y.J., et al., EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency, Mol. Cell, 2008, vol. 32, no. 4, pp. 491—502. https://doi.org/10.1016/j.molcel.2008.10.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Genta, S., Pirosa, M.C., and Stathis, A., BET and EZH2 inhibitors: novel approaches for targeting cancer, Curr. Oncol. Rep., 2019, vol. 21, no. 2, p. 13. https://doi.org/10.1007/s11912-019-0762-x

    Article  PubMed  Google Scholar 

  29. Richart, L. and Margueron, R., Drugging histone methyltransferases in cancer, Curr. Opin. Chem. Biol., 2020, vol. 56, pp. 51—62. https://doi.org/10.1016/j.cbpa.2019.11.009

    Article  CAS  PubMed  Google Scholar 

  30. Hoy, S.M., Tazemetostat: first approval, Drugs, 2020, vol. 80, no. 5, pp. 513—521. https://doi.org/10.1007/s40265-020-01288-x

    Article  CAS  PubMed  Google Scholar 

  31. Italiano, A., Targeting epigenetics in sarcomas through EZH2 inhibition, J. Hematol. Oncol., 2020, vol. 13, no. 1, p. 33. https://doi.org/10.1186/s13045-020-00868-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rothbart, S.B. and Baylin, S.B., Epigenetic therapy for epithelioid sarcoma, Cell, 2020, vol. 181, no. 2, p. 211. https://doi.org/10.1016/j.cell.2020.03.042

    Article  CAS  PubMed  Google Scholar 

  33. Comet, I., Riising, E.M., Leblanc, B., and Helin, K., Maintaining cell identity: PRC2-mediated regulation of transcription and cancer, Nat. Rev. Cancer, 2016, vol. 16, no. 12, pp. 803—810. https://doi.org/10.1038/nrc.2016.83

    Article  CAS  PubMed  Google Scholar 

  34. Kim, K.H. and Roberts, C.W., Targeting EZH2 in cancer, Nat. Med., 2016, vol. 22, no. 2, pp. 128—134. https://doi.org/10.1038/nm.4036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lue, J.K. and Amengual, J.E., Emerging EZH2 inhibitors and their application in lymphoma, Curr. Hematol. Malig. Rep., 2018, vol. 13, no. 5, pp. 369—382. https://doi.org/10.1007/s11899-018-0466-6

    Article  PubMed  Google Scholar 

  36. Yamagishi, M. and Uchimaru, K., Targeting EZH2 in cancer therapy, Curr. Opin. Oncol., 2017, vol. 29, no. 5, pp. 375—381. https://doi.org/10.1097/CCO.0000000000000390

    Article  CAS  PubMed  Google Scholar 

  37. Bracken, A.P., Pasini, D., Capra, M., et al., EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer, EMBO J., 2003, vol. 22, no. 20, pp. 5323—5335. https://doi.org/10.1093/emboj/cdg542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lee, S.R., Roh, Y.G., Kim, S.K., et al., Activation of EZH2 and SUZ12 regulated by E2F1 predicts the disease progression and aggressive characteristics of bladder cancer, Clin. Cancer Res., 2015, vol. 21, no. 23, pp. 5391—5403. https://doi.org/10.1158/1078-0432.CCR-14-2680

    Article  CAS  PubMed  Google Scholar 

  39. Takawa, M., Masuda, K., Kunizaki, M., et al., Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker, Cancer Sci., 2011, vol. 102, no. 7, pp. 1298—1305. https://doi.org/10.1111/j.1349-7006.2011.01958.x

    Article  CAS  PubMed  Google Scholar 

  40. Okosun, J., Bodor, C., Wang, J., et al., Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma, Nat. Genet., 2014, vol. 46, no. 2, pp. 176—181. https://doi.org/10.1038/ng.2856

    Article  CAS  PubMed  Google Scholar 

  41. Kienle, D., Katzenberger, T., Ott, G., et al., Quantitative gene expression deregulation in mantle-cell lymphoma: correlation with clinical and biologic factors, J. Clin. Oncol., 2007, vol. 25, no. 19, pp. 2770—2777. https://doi.org/10.1200/JCO.2006.08.7999

    Article  CAS  PubMed  Google Scholar 

  42. Lin, Y.L., Zou, Z.K., Su, H.Y., and Huang, Y.Q., Expression of MiR101 and EZH2 in patients with mantle cell lymphoma and its clinical significance, Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2019, vol. 27, no. 3, pp. 820—826. https://doi.org/10.19746/j.cnki.issn.1009-2137.2019.03.029

    Article  PubMed  Google Scholar 

  43. Yan, J., Ng, S.B., Tay, J.L., et al., EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity, Blood, 2013, vol. 121, no. 22, pp. 4512—4520. https://doi.org/10.1182/blood-2012-08-450494

    Article  CAS  PubMed  Google Scholar 

  44. Pawlyn, C., Bright, M.D., Buros, A.F., et al., Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control, Blood Cancer J., 2017, vol. 7, no. 3. e549. https://doi.org/10.1038/bcj.2017.27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wilson, B.G., Wang, X., Shen, X., et al., Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation, Cancer Cell, 2010, vol. 18, no. 4, pp. 316—328. https://doi.org/10.1016/j.ccr.2010.09.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bachmann, I.M., Halvorsen, O.J., Collett, K., 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., 2006, vol. 24, no. 2, pp. 268—273. https://doi.org/10.1200/JCO.2005.01.5180

    Article  CAS  PubMed  Google Scholar 

  47. Collett, K., Eide, G.E., Arnes, J., et al., Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer, Clin. Cancer Res., 2006, vol. 12, no. 4, pp. 1168—1174. https://doi.org/10.1158/1078-0432.CCR-05-1533

    Article  CAS  PubMed  Google Scholar 

  48. Gonzalez, M.E., Moore, H.M., Li, X., et al., EZH2 expands breast stem cells through activation of NOTCH1 signaling, Proc. Natl. Acad. Sci. U.S.A., 2014, vol. 111, no. 8, pp. 3098—3103. https://doi.org/10.1073/pnas.1308953111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kleer, C.G., Cao, Q., Varambally, S., et al., EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells, Proc. Natl. Acad. Sci. U.S.A., 2003, vol. 100, no. 20, pp. 11606—11611. https://doi.org/10.1073/pnas.1933744100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pietersen, A.M., Horlings, H.M., Hauptmann, M., et al., EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer, Breast Cancer Res., 2008, vol. 10, no. 6, p. R109. https://doi.org/10.1186/bcr2214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Puppe, J., Drost, R., Liu, X., et al., BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A, Breast Cancer Res., 2009, vol. 11, no. 4, p. R63. https://doi.org/10.1186/bcr2354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yu, H., Simons, D.L., Segall, I., et al., PRC2/EED-EZH2 complex is up-regulated in breast cancer lymph node metastasis compared to primary tumor and correlates with tumor proliferation in situ, PLoS One, 2012, vol. 7, no. 12. e51239. https://doi.org/10.1371/journal.pone.0051239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liu, Y.L., Gao, X., Jiang, Y., et al., Expression and clinicopathological significance of EED, SUZ12 and EZH2 mRNA in colorectal cancer, J. Cancer Res. Clin. Oncol., 2015, vol. 141, no. 4, pp. 661—669. https://doi.org/10.1007/s00432-014-1854-5

    Article  CAS  PubMed  Google Scholar 

  54. Ohuchi, M., Sakamoto, Y., Tokunaga, R., et al., Increased EZH2 expression during the adenoma—carcinoma sequence in colorectal cancer, Oncol. Lett., 2018, vol. 16, no. 4, pp. 5275—5281. https://doi.org/10.3892/ol.2018.9240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang, C.G., Ye, Y.J., Yuan, J., et al., EZH2 and STAT6 expression profiles are correlated with colorectal cancer stage and prognosis, World J. Gastroenterol., 2010, vol. 16, no. 19, pp. 2421—2427. https://doi.org/10.3748/wjg.v16.i19.2421

    Article  PubMed  PubMed Central  Google Scholar 

  56. He, L.J., Cai, M.Y., Xu, G.L., et al., Prognostic significance of overexpression of EZH2 and H3k27me3 proteins in gastric cancer, Asian Pac. J. Cancer Prev., 2012, vol. 13, no. 7, pp. 3173—3178. https://doi.org/10.7314/apjcp.2012.13.7.3173

    Article  PubMed  Google Scholar 

  57. Pan, Y.M., Wang, C.G., Zhu, M., et al., STAT3 signaling drives EZH2 transcriptional activation and mediates poor prognosis in gastric cancer, Mol. Cancer, 2016, vol. 15, no. 1, p. 79. https://doi.org/10.1186/s12943-016-0561-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lei, Q., Shen, F., Wu, J., et al., MiR-101, downregulated in retinoblastoma, functions as a tumor suppressor in human retinoblastoma cells by targeting EZH2, Oncol. Rep., 2014, vol. 32, no. 1, pp. 261—269. https://doi.org/10.3892/or.2014.3167

    Article  CAS  PubMed  Google Scholar 

  59. Wagener, N., Macher-Goeppinger, S., Pritsch, M., et al., Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma, BMC Cancer, 2010, vol. 10, p. 524. https://doi.org/10.1186/1471-2407-10-524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang, M.J., Chen, D.S., Li, H., et al., Clinical significance of USP7 and EZH2 in predicting prognosis of laryngeal squamous cell carcinoma and their possible functional mechanism, Int. J. Clin. Exp. Pathol., 2019, vol. 12, no. 6, pp. 2184—2194.

    PubMed  PubMed Central  Google Scholar 

  61. Sudo, T., Utsunomiya, T., Mimori, K., et al., Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma, Br. J. Cancer, 2005, vol. 92, no. 9, pp. 1754—1758. https://doi.org/10.1038/sj.bjc.6602531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Nakagawa, S., Okabe, H., Sakamoto, Y., et al., Enhancer of zeste homolog 2 (EZH2) promotes progression of cholangiocarcinoma cells by regulating cell cycle and apoptosis, Ann. Surg. Oncol., 2013, vol. 20, suppl 3, pp. S667—S675. https://doi.org/10.1245/s10434-013-3135-y

    Article  PubMed  Google Scholar 

  63. Cao, W., Ribeiro, RdeO., Liu, D., et al., EZH2 promotes malignant behaviors via cell cycle dysregulation and its mRNA level associates with prognosis of patient with non-small cell lung cancer, PLoS One, 2012, vol. 7, no. 12. e52984. https://doi.org/10.1371/journal.pone.0052984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kikuchi, J., Kinoshita, I., Shimizu, Y., et al., Distinctive expression of the polycomb group proteins Bmi1 polycomb ring finger oncogene and enhancer of zeste homolog 2 in nonsmall cell lung cancers and their clinical and clinicopathologic significance, Cancer, 2010, vol. 116, no. 12, pp. 3015—3024. https://doi.org/10.1002/cncr.25128

    Article  CAS  PubMed  Google Scholar 

  65. Liu, H., Li, W., Yu, X., et al., EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis, Oncotarget, 2016, vol. 7, no. 35, pp. 56338—56354. https://doi.org/10.18632/oncotarget.10841

    Article  PubMed  PubMed Central  Google Scholar 

  66. Ciarapica, R., Russo, G., Verginelli, F., et al., Deregulated expression of miR-26a and Ezh2 in rhabdomyosarcoma, Cell Cycle, 2009, vol. 8, no. 1, pp. 172—175. https://doi.org/10.4161/cc.8.1.7292

    Article  CAS  PubMed  Google Scholar 

  67. Li, H., Cai, Q., Godwin, A.K., and Zhang, R., Enhancer of zeste homolog 2 promotes the proliferation and invasion of epithelial ovarian cancer cells, Mol. Cancer Res., 2010, vol. 8, no. 12, pp. 1610—1618. https://doi.org/10.1158/1541-7786.MCR-10-0398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Li, H., Cai, Q., Wu, H., et al., SUZ12 promotes human epithelial ovarian cancer by suppressing apoptosis via silencing HRK, Mol. Cancer Res., 2012, vol. 10, no. 11, pp. 1462—1472. https://doi.org/10.1158/1541-7786.MCR-12-0335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lu, C., Han, H.D., Mangala, L.S., et al., Regulation of tumor angiogenesis by EZH2, Cancer Cell, 2010, vol. 18, no. 2, pp. 185—197. https://doi.org/10.1016/j.ccr.2010.06.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Crea, F., Hurt, E.M., Mathews, L.A., et al., Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancer, Mol. Cancer, 2011, vol. 10, p. 40. https://doi.org/10.1186/1476-4598-10-40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Varambally, S., Dhanasekaran, S.M., Zhou, M., et al., The polycomb group protein EZH2 is involved in progression of prostate cancer, Nature, 2002, vol. 419, no. 6907, pp. 624—629. https://doi.org/10.1038/nature01075

    Article  CAS  PubMed  Google Scholar 

  72. Saramaki, O.R., Tammela, T.L., Martikainen, P.M., et al., The gene for polycomb group protein enhancer of zeste homolog 2 (EZH2) is amplified in late-stage prostate cancer, Genes Chromosomes Cancer, 2006, vol. 45, no. 7, pp. 639—645. https://doi.org/10.1002/gcc.20327

    Article  CAS  PubMed  Google Scholar 

  73. Borbone, E., Troncone, G., Ferraro, A., et al., Enhancer of zeste homolog 2 overexpression has a role in the development of anaplastic thyroid carcinomas, J. Clin. Endocrinol. Metab., 2011, vol. 96, no. 4, pp. 1029—1038. https://doi.org/10.1210/jc.2010-1784

    Article  CAS  PubMed  Google Scholar 

  74. Masudo, K., Suganuma, N., Nakayama, H., et al., EZH2 overexpression as a useful prognostic marker for aggressive behaviour in thyroid cancer, In Vivo, 2018, vol. 32, no. 1, pp. 25—31. https://doi.org/10.21873/invivo.11200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Azizmohammadi, S., Azizmohammadi, S., Safari, A., et al., High-level expression of RIPK4 and EZH2 contributes to lymph node metastasis and predicts favorable prognosis in patients with cervical cancer, Oncol. Res., 2017, vol. 25, no. 4, pp. 495—501. https://doi.org/10.3727/096504016X14749735594687

    Article  PubMed  PubMed Central  Google Scholar 

  76. Jia, N., Li, Q., Tao, X., et al., Enhancer of zeste homolog 2 is involved in the proliferation of endometrial carcinoma, Oncol. Lett., 2014, vol. 8, no. 5, pp. 2049—2054. https://doi.org/10.3892/ol.2014.2437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Abudurexiti, M., Xie, H., Jia, Z., et al., Development and external validation of a novel 12-gene signature for prediction of overall survival in muscle-invasive bladder cancer, Front. Oncol., 2019, vol. 9, p. 856. https://doi.org/10.3389/fonc.2019.00856

    Article  PubMed  PubMed Central  Google Scholar 

  78. Martin-Perez, D., Sanchez, E., Maestre, L., et al., Deregulated expression of the polycomb-group protein SUZ12 target genes characterizes mantle cell lymphoma, Am. J. Pathol., 2010, vol. 177, no. 2, pp. 930—942. https://doi.org/10.2353/ajpath.2010.090769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Iliopoulos, D., Lindahl-Allen, M., Polytarchou, C., et al., Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells, Mol. Cell, 2010, vol. 39, no. 5, pp. 761—772. https://doi.org/10.1016/j.molcel.2010.08.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Xia, R., Jin, F.Y., Lu, K., et al., SUZ12 promotes gastric cancer cell proliferation and metastasis by regulating KLF2 and E-cadherin, Tumour Biol., 2015, vol. 36, no. 7, pp. 5341—5351. https://doi.org/10.1007/s13277-015-3195-7

    Article  CAS  PubMed  Google Scholar 

  81. Liu, C., Shi, X., Wang, L., et al., SUZ12 is involved in progression of non-small cell lung cancer by promoting cell proliferation and metastasis, Tumour Biol., 2014, vol. 35, no. 6, pp. 6073—6082. https://doi.org/10.1007/s13277-014-1804-5

    Article  CAS  PubMed  Google Scholar 

  82. Bodor, C., Grossmann, V., Popov, N., et al., EZH2 mutations are frequent and represent an early event in follicular lymphoma, Blood, 2013, vol. 122, no. 18, pp. 3165—3168. https://doi.org/10.1182/blood-2013-04-496893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bodor, C., O’Riain, C., Wrench, D., et al., EZH2 Y641 mutations in follicular lymphoma, Leukemia, 2011, vol. 25, no. 4, pp. 726—729. https://doi.org/10.1038/leu.2010.311

    Article  CAS  PubMed  Google Scholar 

  84. Lohr, J.G., Stojanov, P., Lawrence, M.S., et al., Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing, Proc. Natl. Acad. Sci. U.S.A., 2012, vol. 109, no. 10, pp. 3879—3884. https://doi.org/10.1073/pnas.1121343109

    Article  PubMed  PubMed Central  Google Scholar 

  85. Majer, C.R., Jin, L., Scott, M.P., et al., A687V EZH2 is a gain-of-function mutation found in lymphoma patients, FEBS Lett., 2012, vol. 586, no. 19, pp. 3448—3451. https://doi.org/10.1016/j.febslet.2012.07.066

    Article  CAS  PubMed  Google Scholar 

  86. Morin, R.D., Johnson, N.A., Severson, T.M., et al., Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin, Nat. Genet., 2010, vol. 42, no. 2, pp. 181—185. https://doi.org/10.1038/ng.518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Morin, R.D., Mendez-Lago, M., Mungall, A.J., et al., Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma, Nature, 2011, vol. 476, no. 7360, pp. 298—303. https://doi.org/10.1038/nature10351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Reddy, A., Zhang, J., Davis, N.S., et al., Genetic and functional drivers of diffuse large B cell lymphoma, Cell, 2017, vol. 171, no. 2, pp. 481—494. e415. https://doi.org/10.1016/j.cell.2017.09.027

  89. Ryan, R.J., Nitta, M., Borger, D., et al., EZH2 codon 641 mutations are common in BCL2-rearranged germinal center B cell lymphomas, PLoS One, 2011, vol. 6, no. 12. e28585. https://doi.org/10.1371/journal.pone.0028585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Calebiro, D., Grassi, E.S., Eszlinger, M., et al., Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas, J. Clin. Invest., 2016, vol. 126, no. 9, pp. 3383—3388. https://doi.org/10.1172/JCI84894

    Article  PubMed  PubMed Central  Google Scholar 

  91. Ntziachristos, P., Tsirigos, A., Van Vlierberghe, P., et al., Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia, Nat. Med., 2012, vol. 18, no. 2, pp. 298—301. https://doi.org/10.1038/nm.2651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhang, J., Ding, L., Holmfeldt, L., et al., The genetic basis of early T-cell precursor acute lymphoblastic leukaemia, Nature, 2012, vol. 481, no. 7380, pp. 157—163. https://doi.org/10.1038/nature10725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Puda, A., Milosevic, J.D., Berg, T., et al., Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies, Am. J. Hematol., 2012, vol. 87, no. 3, pp. 245—250. https://doi.org/10.1002/ajh.22257

    Article  CAS  PubMed  Google Scholar 

  94. Bejar, R., Stevenson, K., Abdel-Wahab, O., et al., Clinical effect of point mutations in myelodysplastic syndromes, N. Engl. J. Med., 2011, vol. 364, no. 26, pp. 2496—2506. https://doi.org/10.1056/NEJMoa1013343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ernst, T., Chase, A.J., Score, J., et al., Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders, Nat. Genet., 2010, vol. 42, no. 8, pp. 722—726. https://doi.org/10.1038/ng.621

    Article  CAS  PubMed  Google Scholar 

  96. Guglielmelli, P., Biamonte, F., Score, J., et al., EZH2 mutational status predicts poor survival in myelofibrosis, Blood, 2011, vol. 118, no. 19, pp. 5227—5234. https://doi.org/10.1182/blood-2011-06-363424

    Article  CAS  PubMed  Google Scholar 

  97. Khan, S.N., Jankowska, A.M., Mahfouz, R., et al., Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies, Leukemia, 2013, vol. 27, no. 6, pp. 1301—1309. https://doi.org/10.1038/leu.2013.80

    Article  CAS  PubMed  Google Scholar 

  98. Nikoloski, G., Langemeijer, S.M., Kuiper, R.P., et al., Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes, Nat. Genet., 2010, vol. 42, no. 8, pp. 665—667. https://doi.org/10.1038/ng.620

    Article  CAS  PubMed  Google Scholar 

  99. Zhang, Q., Han, Q., Zi, J., et al., Mutations in EZH2 are associated with poor prognosis for patients with myeloid neoplasms, Genes Dis., 2019, vol. 6, no. 3, pp. 276—281. https://doi.org/10.1016/j.gendis.2019.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Score, J., Hidalgo-Curtis, C., Jones, A.V., et al., Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms, Blood, 2012, vol. 119, no. 5, pp. 1208—1213. https://doi.org/10.1182/blood-2011-07-367243

    Article  CAS  PubMed  Google Scholar 

  101. De Raedt, T., Beert, E., Pasmant, E., et al., PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies, Nature, 2014, vol. 514, no. 7521, pp. 247—251. https://doi.org/10.1038/nature13561

    Article  CAS  PubMed  Google Scholar 

  102. Lee, W., Teckie, S., Wiesner, T., et al., PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors, Nat. Genet., 2014, vol. 46, no. 11, pp. 1227—1232. https://doi.org/10.1038/ng.3095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhang, M., Wang, Y., Jones, S., et al., Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors, Nat. Genet., 2014, vol. 46, no. 11, pp. 1170—1172. https://doi.org/10.1038/ng.3116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Koontz, J.I., Soreng, A.L., Nucci, M., et al., Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors, Proc. Natl. Acad. Sci. U.S.A., 2001, vol. 98, no. 11, pp. 6348—6353. https://doi.org/10.1073/pnas.101132598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Li, H., Ma, X., Wang, J., et al., Effects of rearrangement and allelic exclusion of JJAZ1/SUZ12 on cell proliferation and survival, Proc. Natl. Acad. Sci. U.S.A., 2007, vol. 104, no. 50, pp. 20001—20006. https://doi.org/10.1073/pnas.0709986104

    Article  PubMed  PubMed Central  Google Scholar 

  106. Ma, X., Wang, J., Wang, J., et al., The JAZF1-SUZ12 fusion protein disrupts PRC2 complexes and impairs chromatin repression during human endometrial stromal tumorogenesis, Oncotarget, 2017, vol. 8, no. 3, pp. 4062—4078. https://doi.org/10.18632/oncotarget.13270

    Article  PubMed  Google Scholar 

  107. Makise, N., Sekimizu, M., Kobayashi, E., et al., Low-grade endometrial stromal sarcoma with a novel MEAF6-SUZ12 fusion, Virchows Arch., 2019, vol. 475, no. 4, pp. 527—531. https://doi.org/10.1007/s00428-019-02588-8

    Article  CAS  PubMed  Google Scholar 

  108. Ueda, T., Sanada, M., Matsui, H., et al., EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms, Leukemia, 2012, vol. 26, no. 12, pp. 2557—2560. https://doi.org/10.1038/leu.2012.146

    Article  CAS  PubMed  Google Scholar 

  109. Boileau, M., Shirinian, M., Gayden, T., et al., Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness, Nat. Commun., 2019, vol. 10, no. 1, p. 2891. https://doi.org/10.1038/s41467-019-10705-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Schwartzentruber, J., Korshunov, A., Liu, X.Y., et al., Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma, Nature, 2012, vol. 482, no. 7384, pp. 226—231. https://doi.org/10.1038/nature10833

    Article  CAS  PubMed  Google Scholar 

  111. Sturm, D., Witt, H., Hovestadt, V., et al., Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma, Cancer Cell, 2012, vol. 22, no. 4, pp. 425—437. https://doi.org/10.1016/j.ccr.2012.08.024

    Article  CAS  PubMed  Google Scholar 

  112. Wu, G., Broniscer, A., McEachron, T.A., et al., Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas, Nat. Genet., 2012, vol. 44, no. 3, pp. 251—253. https://doi.org/10.1038/ng.1102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. McCabe, M.T., Graves, A.P., 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, vol. 109, no. 8, pp. 2989—2994. https://doi.org/10.1073/pnas.1116418109

    Article  PubMed  PubMed Central  Google Scholar 

  114. Ott, H.M., Graves, A.P., Pappalardi, M.B., et al., A687V EZH2 is a driver of histone H3 lysine 27 (H3K27) hypertrimethylation, Mol. Cancer Ther., 2014, vol. 13, no. 12, pp. 3062—3073. https://doi.org/10.1158/1535-7163.MCT-13-0876

    Article  CAS  PubMed  Google Scholar 

  115. Sneeringer, C.J., Scott, M.P., Kuntz, K.W., 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. U.S.A., 2010, vol. 107, no. 49, pp. 20980—20985. https://doi.org/10.1073/pnas.1012525107

    Article  PubMed  PubMed Central  Google Scholar 

  116. Yap, D.B., Chu, J., Berg, T., et al., Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation, Blood, 2011, vol. 117, no. 8, pp. 2451—2459. https://doi.org/10.1182/blood-2010-11-321208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Beguelin, W., Popovic, R., Teater, M., et al., EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation, Cancer Cell, 2013, vol. 23, no. 5, pp. 677—692. https://doi.org/10.1016/j.ccr.2013.04.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chang, C.J., Yang, J.Y., Xia, W., et al., EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling, Cancer Cell, 2011, vol. 19, no. 1, pp. 86—100. https://doi.org/10.1016/j.ccr.2010.10.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Herrera-Merchan, A., Arranz, L., Ligos, J.M., et al., Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease, Nat. Commun., 2012, vol. 3, p. 623. https://doi.org/10.1038/ncomms1623

    Article  CAS  PubMed  Google Scholar 

  120. Min, J., Zaslavsky, A., Fedele, G., et al., An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB, Nat. Med., 2010, vol. 16, no. 3, pp. 286—294. https://doi.org/10.1038/nm.2100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Berg, T., Thoene, S., Yap, D., et al., A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis, Blood, 2014, vol. 123, no. 25, pp. 3914—3924. https://doi.org/10.1182/blood-2012-12-473439

    Article  CAS  PubMed  Google Scholar 

  122. Amatangelo, M.D., Garipov, A., Li, H., et al., Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition, Cell Cycle, 2013, vol. 12, no. 13, pp. 2113—2119. https://doi.org/10.4161/cc.25163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kim, W., Bird, G.H., Neff, T., et al., Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer, Nat. Chem. Biol., 2013, vol. 9, no. 10, pp. 643—650. https://doi.org/10.1038/nchembio.1331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Knutson, S.K., Warholic, N.M., Wigle, T.J., et al., Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2, Proc. Natl. Acad. Sci. U.S.A., 2013, vol. 110, no. 19, pp. 7922—7927. https://doi.org/10.1073/pnas.1303800110

    Article  PubMed  PubMed Central  Google Scholar 

  125. Neff, T., Sinha, A.U., Kluk, M.J., et al., Polycomb repressive complex 2 is required for MLL-AF9 leukemia, Proc. Natl. Acad. Sci. U.S.A., 2012, vol. 109, no. 13, pp. 5028—5033. https://doi.org/10.1073/pnas.1202258109

    Article  PubMed  PubMed Central  Google Scholar 

  126. Shi, J., Wang, E., Zuber, J., et al., The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;Nras(G12D) acute myeloid leukemia, Oncogene, 2013, vol. 32, no. 7, pp. 930—938. https://doi.org/10.1038/onc.2012.110

    Article  CAS  PubMed  Google Scholar 

  127. Tanaka, S., Miyagi, S., Sashida, G., et al., Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia, Blood, 2012, vol. 120, no. 5, pp. 1107—1117. https://doi.org/10.1182/blood-2011-11-394932

    Article  CAS  PubMed  Google Scholar 

  128. Bender, S., Tang, Y., Lindroth, A.M., et al., Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas, Cancer Cell, 2013, vol. 24, no. 5, pp. 660—672. https://doi.org/10.1016/j.ccr.2013.10.006

    Article  CAS  PubMed  Google Scholar 

  129. Chan, K.M., Fang, D., Gan, H., et al., The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression, Genes Dev., 2013, vol. 27, no. 9, pp. 985—990. https://doi.org/10.1101/gad.217778.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Justin, N., Zhang, Y., Tarricone, C., et al., Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2, Nat. Commun., 2016, vol. 7, p. 11316. https://doi.org/10.1038/ncomms11316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lewis, P.W., Muller, M.M., Koletsky, M.S., et al., Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma, Science, 2013, vol. 340, no. 6134, pp. 857—861. https://doi.org/10.1126/science.1232245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Lee, C.H., Yu, J.R., Granat, J., et al., Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma, Genes Dev., 2019, vol. 33, nos. 19–20, pp. 1428—1440. https://doi.org/10.1101/gad.328773.119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Hubner, J.M., Muller, T., Papageorgiou, D.N., et al., EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma, Neuro. Oncol., 2019, vol. 21, no. 7, pp. 878—889. https://doi.org/10.1093/neuonc/noz058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Jain, S.U., Do, T.J., Lund, P.J., et al., PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism, Nat. Commun., 2019, vol. 10, no. 1, p. 2146. https://doi.org/10.1038/s41467-019-09981-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Piunti, A., Smith, E.R., Morgan, M.A.J., et al., CATACOMB: an endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism, Sci. Adv., 2019, vol. 5, no. 7, p. eaax2887. https://doi.org/10.1126/sciadv.aax2887

  136. Ragazzini, R., Perez-Palacios, R., Baymaz, I.H., et al., EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells, Nat. Commun., 2019, vol. 10, no. 1, p. 3858. https://doi.org/10.1038/s41467-019-11800-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Abdel-Wahab, O. and Dey, A., The ASXL-BAP1 axis: new factors in myelopoiesis, cancer and epigenetics, Leukemia, 2013, vol. 27, no. 1, pp. 10—15. https://doi.org/10.1038/leu.2012.288

    Article  CAS  PubMed  Google Scholar 

  138. Danis, E., Yamauchi, T., Echanique, K., et al., Ezh2 controls an early hematopoietic program and growth and survival signaling in early T cell precursor acute lymphoblastic leukemia, Cell Rep., 2016, vol. 14, no. 8, pp. 1953—1965. https://doi.org/10.1016/j.celrep.2016.01.064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Booth, C.A.G., Barkas, N., Neo, W.H., et al., Ezh2 and Runx1 mutations collaborate to initiate lympho-myeloid leukemia in early thymic progenitors, Cancer Cell, 2018, vol. 33, no. 2, pp. 274—291. e278. https://doi.org/10.1016/j.ccell.2018.01.006

  140. Wang, C., Oshima, M., Sato, D., et al., Ezh2 loss propagates hypermethylation at T cell differentiation-regulating genes to promote leukemic transformation, J. Clin. Invest., 2018, vol. 128, no. 9, pp. 3872—3886. https://doi.org/10.1172/JCI94645

    Article  PubMed  PubMed Central  Google Scholar 

  141. Broux, M., Prieto, C., Demeyer, S., et al., Suz12 inactivation cooperates with JAK3 mutant signaling in the development of T-cell acute lymphoblastic leukemia, Blood, 2019, vol. 134, no. 16, pp. 1323—1336. https://doi.org/10.1182/blood.2019000015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Abdel-Wahab, O., Adli, M., LaFave, L.M., et al., ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression, Cancer Cell, 2012, vol. 22, no. 2, pp. 180—193. https://doi.org/10.1016/j.ccr.2012.06.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Lane, A.A., Chapuy, B., Lin, C.Y., et al., Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation, Nat. Genet., 2014, vol. 46, no. 6, pp. 618—623. https://doi.org/10.1038/ng.2949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 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, vol. 5, p. 4177. https://doi.org/10.1038/ncomms5177

    Article  CAS  PubMed  Google Scholar 

  145. Maertens, O. and Cichowski, K., An expanding role for RAS GTPase activating proteins (RAS GAPs) in cancer, Adv. Biol. Regul., 2014, vol. 55, pp. 1—14. https://doi.org/10.1016/j.jbior.2014.04.002

    Article  CAS  PubMed  Google Scholar 

  146. Simon, C., Chagraoui, J., Krosl, J., et al., A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia, Genes Dev., 2012, vol. 26, no. 7, pp. 651—656. https://doi.org/10.1101/gad.186411.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Souroullas, G.P., Jeck, W.R., Parker, J.S., et al., An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation, Nat. Med., 2016, vol. 22, no. 6, pp. 632—640. https://doi.org/10.1038/nm.4092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Tan, J., Yang, X., Zhuang, L., et al., Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells, Genes Dev., 2007, vol. 21, no. 9, pp. 1050—1063. https://doi.org/10.1101/gad.1524107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Miranda, T.B., Cortez, C.C., Yoo, C.B., et al., DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation, Mol. Cancer Ther., 2009, vol. 8, no. 6, pp. 1579—1588. https://doi.org/10.1158/1535-7163.MCT-09-0013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Knutson, S.K., Wigle, T.J., Warholic, N.M., et al., A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells, Nat. Chem. Biol., 2012, vol. 8, no. 11, pp. 890—896. https://doi.org/10.1038/nchembio.1084

    Article  CAS  PubMed  Google Scholar 

  151. McCabe, M.T., Ott, H.M., Ganji, G., et al., EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations, Nature, 2012, vol. 492, no. 7427, pp. 108—112. https://doi.org/10.1038/nature11606

    Article  CAS  PubMed  Google Scholar 

  152. 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, vol. 109, no. 52, pp. 21360—21365. https://doi.org/10.1073/pnas.1210371110

    Article  PubMed  PubMed Central  Google Scholar 

  153. Knutson, S.K., Kawano, S., Minoshima, Y., et al., Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma, Mol. Cancer Ther., 2014, vol. 13, no. 4, pp. 842—854. https://doi.org/10.1158/1535-7163.MCT-13-0773

    Article  CAS  PubMed  Google Scholar 

  154. Konze, K.D., Ma, A., Li, F., et al., An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1, ACS Chem. Biol., 2013, vol. 8, no. 6, pp. 1324—1334. https://doi.org/10.1021/cb400133j

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Fujita, S., Honma, D., Adachi, N., et al., Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia, Leukemia, 2018, vol. 32, no. 4, pp. 855—864. https://doi.org/10.1038/leu.2017.300

    Article  CAS  PubMed  Google Scholar 

  156. 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, vol. 108, no. 10, pp. 2069—2078. https://doi.org/10.1111/cas.13326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. He, Y., Selvaraju, S., Curtin, M.L., et al., The EED protein—protein interaction inhibitor A-395 inactivates the PRC2 complex, Nat. Chem. Biol., 2017, vol. 13, no. 4, pp. 389—395. https://doi.org/10.1038/nchembio.2306

    Article  CAS  PubMed  Google Scholar 

  158. Qi, W., Zhao, K., Gu, J., et al., An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED, Nat. Chem. Biol., 2017, vol. 13, no. 4, pp. 381—388. https://doi.org/10.1038/nchembio.2304

    Article  CAS  PubMed  Google Scholar 

  159. Ma, A., Stratikopoulos, E., Park, K.S., et al., Discovery of a first-in-class EZH2 selective degrader, Nat. Chem. Biol., 2020, vol. 16, no. 2, pp. 214—222. https://doi.org/10.1038/s41589-019-0421-4

    Article  CAS  PubMed  Google Scholar 

  160. Versteege, I., Sevenet, N., Lange, J., et al., Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer, Nature, 1998, vol. 394, no. 6689, pp. 203—206. https://doi.org/10.1038/28212

    Article  CAS  PubMed  Google Scholar 

  161. Kohashi, K. and Oda, Y., Oncogenic roles of SMARCB1/INI1 and its deficient tumors, Cancer Sci., 2017, vol. 108, no. 4, pp. 547—552. https://doi.org/10.1111/cas.13173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Jiao, L. and Liu, X., Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2, Science, 2015, vol. 350, no. 6258, p. aac4383. https://doi.org/10.1126/science.aac4383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Kasinath, V., Faini, M., Poepsel, S., et al., Structures of human PRC2 with its cofactors AEBP2 and JARID2, Science, 2018, vol. 359, no. 6378, pp. 940—944. https://doi.org/10.1126/science.aar5700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Khan, M., Walters, L.L., Li, Q., et al., Characterization and pharmacologic targeting of EZH2, a fetal retinal protein and epigenetic regulator, in human retinoblastoma, Lab. Invest., 2015, vol. 95, no. 11, pp. 1278—1290. https://doi.org/10.1038/labinvest.2015.104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Lai, A.C. and Crews, C.M., Induced protein degradation: an emerging drug discovery paradigm, Nat. Rev. Drug. Discov., 2017, vol. 16, no. 2, pp. 101—114. https://doi.org/10.1038/nrd.2016.211

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by the Russian Science Foundation (grant no. 18-74-10091).

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Authors and Affiliations

  1. Institute of Gene Biology, Russian Academy of Sciences, 119334, Moscow, Russia

    D. A. Chetverina, D. V. Lomaev, P. G. Georgiev & M. M. Erokhin

Authors
  1. D. A. Chetverina
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  2. D. V. Lomaev
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  3. P. G. Georgiev
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  4. M. M. Erokhin
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Correspondence to M. M. Erokhin.

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Conflict of interest. The authors declare that they have no conflicts of interest.

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Translated by N. Maleeva

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Chetverina, D.A., Lomaev, D.V., Georgiev, P.G. et al. Genetic Impairments of PRC2 Activity in Oncology: Problems and Prospects. Russ J Genet 57, 258–272 (2021). https://doi.org/10.1134/S1022795421030042

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  • DOI: https://doi.org/10.1134/S1022795421030042

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