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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.
Highlights
Endometriosis is an estrogen-dependent disorder and a major contributor to pelvic pain and subfertility, affecting 6–10% of women of reproductive age[1]
We found that Deazaneplanocin A (DZNep) significantly abrogated the expression of Enhancer of Zeste homolog 2 (EZH2), ectoderm development (EED), suppressor of zeste 12 (SUZ12), H3K9me[3], H3K27me[3], α-SMA and collagen I while elevated E-cadherin expression in ectopic endometrial epithelial cells, all in a dose-dependent manner (all p-values < 0.0005 based on and quantification of lesion weight (D) in mice with induced endometriosis treated with DZNep or vehicle. (E) Quantitative comparison of EZH2, EED, SUZ12, H3K27me[3], H3K9me[3], E-cadherin, α-SMA and Collagen I
We found that the expression of EZH2 and its associated polycomb repressive complex 2 (PRC2) proteins, along with H3K9me[3] and H3K27me[3], are elevated in endometriosis
Summary
Endometriosis is an estrogen-dependent disorder and a major contributor to pelvic pain and subfertility, affecting 6–10% of women of reproductive age[1]. We have recently demonstrated that, because of this hallmark, endometriotic lesions are essentially wounds that undergo repeated tissue injury and repair (ReTIAR), resulting in platelet-driven epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), smooth muscle metaplasia (SMM) and fibrosis[7, 8]. EMT occurs in endometriosis, most likely not because of the increased invasiveness of endometriotic cells per se[10], but because of an innate physiological response to injury due to the nature of lesions undergoing ReTIAR9.
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