Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

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.

Ezh2, endothelin-1, and cd34 as biomarkers of aggressive cervical squamous cell carcinoma: an immunohistochemical study

“…PRC2 methylated lysine 27 of histone H3 (H3K27) and lysine 9 of histone H3 (H3K9) to induce transcriptional silencing. EZH2 can induce epithelialmesenchymal transition (EMT) directly by repressing the expression of E-cadherin through histone H3K27 trimethylation, or indirectly by inhibiting miR-361 which is a Twist suppressor (15). This could explain our findings as regards the presence of significant relation between high EZH2 expression and advanced FIGO stage and the presence of lymph node metastasis in CSCC cases.…”

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

“…Or endometriotic cells have developed some mechanisms that elude senescence? Moreover, consistent with the view that fibrogenesis entails epigenetic aberrations, growing evidence indicates that in endometriosis fibrogenesis also involves epigenetic changes . This raises the question as whether hormonal therapeutics can actually modify the epigenetic aberration, resulting in a gradual reverse of fibrogenesis, especially in highly fibrotic lesions such as DE.…”

“…They also secrete many bioactive factors, including thromboxane A2 (TXA 2 ), which may also act as a neutrophin, leading to hyperinnervation within or surround endometriotic lesions . Moreover, platelets may also induce epigenetic changes, facilitating the gradual but progressive development of endometriosis, leading ultimately to tissue fibrosis . Both animal and human data lend support for the notion that endometriotic lesions are fundamentally wounds undergoing repeated tissue injury and repair (ReTIAR) .…”

“…In particular, MeCP2‐mediated enhancer of zeste homolog 2 (EZH2) activation, trimethylation of histone 3 lysine 27 (H3K27me3) and PPARγ suppression have been reported during myofibroblast activation, and in both OMA and DE lesions PPARγ suppression, EZH2 activation and increased H3K27me3 expression have been reported . In fact, EZH2 is found to induce EMT and thus fibrogenesis in endometriosis, and there are signs to indicate that platelet aggregation in lesions may be responsible for EZH2 activation . Importantly, EZH2 may mediate the repression of GSK‐3β and TP53 and promote the activation of the Wnt/β‐catenin signaling pathway .…”

“…Inhibition of EZH2, a histone methyltransferase catalyzing trimethylation of H3K27 and of H3K9 which serve as anchorage points for the recruitment of additional PRC2 proteins, has been shown to attenuate fibrosis through induction of PTEN expression . Interestingly, EZH2, along with its PRC2 partners EED and SUZ12, is found to induce EMT in endometriosis and its expression is elevated in endometriosis, especially in DE lesions that exhibit higher fibrotic content …”