Enhancer of Zeste Homolog 2 (EZH2) Induces Epithelial-mesenchymal Transition in Endometriosis

Overview

Journal Sci Rep

Specialty Science

Date 2017 Jul 30

PMID 28754964

Citations 45

Authors

Qi Zhang

Peixin Dong

Xishi Liu

Noriaki Sakuragi

Sun-Wei Guo

Affiliations

Soon will be listed here.

Abstract

EZH2, a subunit of the polycomb repressive complex 2 (PRC2) catalyzing trimethylation of histone H3 lysine 27 (H3K27), induces epithelial-mesenchymal transition (EMT) in cancers. However, whether EZH2 regulates EMT in endometriosis is unclear. Here, we show that EZH2 expression, along with its associated PRC2 proteins, is significantly elevated in ectopic and eutopic endometrium from women with endometriosis as compared with control endometrium. EZH2 knockdown or inhibition restored the epithelial phenotypes of endometriotic epithelial cells, concomitant with the upregulation of E-cadherin and downregulation of vimentin and transcription factors (Snail and Slug) as well as reduced cellular migratory and invasive propensity. Conversely, overexpression of EZH2 induced the expression of Snail, Slug and vimentin and suppresses E-cadherin expression. In vivo administration of 3-Deazaneplanocin A (DZNep), an EZH2 inhibitor, significantly inhibited the growth of endometriotic lesions and improved generalized hyperalgesia, along with attenuated EMT and reduced fibrosis in endometriosis. Notably, platelets induced EZH2 upregulation and increased H3K27 and H3K9 trimethylation levels in endometriotic epithelial cells. These data identify EZH2 as a novel driver of EMT in endometriosis, implicates the link between wound healing and epigenetic changes in the context of endometriosis, and underscore the role of platelets in the development of endometriosis.

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References

Takeda T, Banno K, Okawa R, Yanokura M, Iijima M, Irie-Kunitomi H . ARID1A gene mutation in ovarian and endometrial cancers (Review). Oncol Rep. 2015; 35(2):607-13. PMC: 4689482. DOI: 10.3892/or.2015.4421. View

Burney R, Giudice L . Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012; 98(3):511-9. PMC: 3836682. DOI: 10.1016/j.fertnstert.2012.06.029. View

Zheng M, Jiang Y, Chen W, Li K, Liu X, Gao S . Snail and Slug collaborate on EMT and tumor metastasis through miR-101-mediated EZH2 axis in oral tongue squamous cell carcinoma. Oncotarget. 2015; 6(9):6797-810. PMC: 4466650. DOI: 10.18632/oncotarget.3180. View

Nisolle M, Donnez J . Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril. 1997; 68(4):585-96. DOI: 10.1016/s0015-0282(97)00191-x. View

Chen Y, Li H, Huang C, Twu N, Yen M, Wang P . Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis. J Pathol. 2010; 222(3):261-70. DOI: 10.1002/path.2761. View

Serrano-Gomez S, Maziveyi M, Alahari S . Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Mol Cancer. 2016; 15:18. PMC: 4765192. DOI: 10.1186/s12943-016-0502-x. View

Guo S, Ding D, Geng J, Wang L, Liu X . P-selectin as a potential therapeutic target for endometriosis. Fertil Steril. 2015; 103(4):990-1000.e8. DOI: 10.1016/j.fertnstert.2015.01.001. View

Sun Q, Ding D, Liu X, Guo S . Tranylcypromine, a lysine-specific demethylase 1 (LSD1) inhibitor, suppresses lesion growth and improves generalized hyperalgesia in mouse with induced endometriosis. Reprod Biol Endocrinol. 2016; 14:17. PMC: 4826530. DOI: 10.1186/s12958-016-0154-0. View

Khan K, Kitajima M, Hiraki K, Fujishita A, Nakashima M, Masuzaki H . Involvement of hepatocyte growth factor-induced epithelial-mesenchymal transition in human adenomyosis. Biol Reprod. 2014; 92(2):35. DOI: 10.1095/biolreprod.114.124891. View

10.

Giudice L, Kao L . Endometriosis. Lancet. 2004; 364(9447):1789-99. DOI: 10.1016/S0140-6736(04)17403-5. View

11.

Guo S, Du Y, Liu X . Platelet-derived TGF-β1 mediates the down-modulation of NKG2D expression and may be responsible for impaired natural killer (NK) cytotoxicity in women with endometriosis. Hum Reprod. 2016; 31(7):1462-74. DOI: 10.1093/humrep/dew057. View

12.

Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C . The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2005; 439(7078):871-4. DOI: 10.1038/nature04431. View

13.

Chang C, Yang J, Xia W, Chen C, Xie X, Chao C . EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-catenin signaling. Cancer Cell. 2011; 19(1):86-100. PMC: 3041516. DOI: 10.1016/j.ccr.2010.10.035. View

14.

Bulun S, Lin Z, Imir G, Amin S, Demura M, Yilmaz B . Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev. 2005; 57(3):359-83. DOI: 10.1124/pr.57.3.6. View

15.

Thiery J, Acloque H, Huang R, Nieto M . Epithelial-mesenchymal transitions in development and disease. Cell. 2009; 139(5):871-90. DOI: 10.1016/j.cell.2009.11.007. View

16.

Kalluri R, Weinberg R . The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119(6):1420-8. PMC: 2689101. DOI: 10.1172/JCI39104. View

17.

Liu X, Shen M, Qi Q, Zhang H, Guo S . Corroborating evidence for platelet-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis. Hum Reprod. 2016; 31(4):734-49. DOI: 10.1093/humrep/dew018. View

18.

Colon-Caraballo M, Monteiro J, Flores I . H3K27me3 is an Epigenetic Mark of Relevance in Endometriosis. Reprod Sci. 2015; 22(9):1134-42. PMC: 5590701. DOI: 10.1177/1933719115578924. View

19.

Xiao X, Senavirathna L, Gou X, Huang C, Liang Y, Liu L . EZH2 enhances the differentiation of fibroblasts into myofibroblasts in idiopathic pulmonary fibrosis. Physiol Rep. 2016; 4(17). PMC: 5027349. DOI: 10.14814/phy2.12915. View

20.

Shen M, Liu X, Zhang H, Guo S . Transforming growth factor β1 signaling coincides with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice. Hum Reprod. 2015; 31(2):355-69. DOI: 10.1093/humrep/dev314. View