Shanghai OB/GYN Hospital, Fudan University, Shanghai, China.
Department of Women's Health Educational System, Hokkaido University, Sapporo, Japan.
Sci Rep. 2017 Jul 28;7(1):6804. doi: 10.1038/s41598-017-06920-7.
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.
EZH2 是多梳抑制复合物 2 (PRC2) 的一个亚基，催化组蛋白 H3 赖氨酸 27 (H3K27) 的三甲基化，诱导癌症中的上皮-间充质转化 (EMT)。然而，EZH2 是否调节子宫内膜异位症中的 EMT 尚不清楚。在这里，我们表明与对照子宫内膜相比，子宫内膜异位症患者的异位和在位子宫内膜中 EZH2 表达及其相关的 PRC2 蛋白显着升高。EZH2 敲低或抑制恢复了子宫内膜异位症上皮细胞的上皮表型，同时上调了 E-钙粘蛋白，下调了波形蛋白和转录因子（Snail 和 Slug），并降低了细胞迁移和侵袭能力。相反，EZH2 的过表达诱导了 Snail、Slug 和波形蛋白的表达，并抑制了 E-钙粘蛋白的表达。体内给予 EZH2 抑制剂 3-去氮杂胞苷（DZNep）可显着抑制子宫内膜异位病变的生长，并改善全身痛觉过敏，同时减弱 EMT 和减少子宫内膜异位症中的纤维化。值得注意的是，血小板诱导 EZH2 上调，并增加子宫内膜异位症上皮细胞中的 H3K27 和 H3K9 三甲基化水平。这些数据确定 EZH2 是子宫内膜异位症中 EMT 的新型驱动因子，提示在子宫内膜异位症背景下伤口愈合与表观遗传变化之间的联系，并强调血小板在子宫内膜异位症发展中的作用。
