Targeting YAP1 ameliorates progesterone resistance in endometriosis

Abstract

STUDY QUESTION Does YAP1 inhibition alleviate progesterone resistance in endometriosis? SUMMARY ANSWER YAP1 inhibition reduces progesterone resistance in vitro and in vivo. WHAT IS KNOWN ALREADY Progesterone resistance not only causes treatment failure for endometriosis but also inhibits eutopic endometrial cell proliferation, dysregulates decidualization, and reduces the success rates of pregnancy. Hippo/yes-associated protein 1 (YAP1) signaling pathway plays an important role in the pathogenesis of endometriosis. STUDY DESIGN, SIZE, DURATION Paraffin-embedded tissues containing paired endometriotic and endometrial specimens (n = 42) and serum samples isolated from normal controls (n = 15) or endometriotic patients with (n = 25) or without (n = 21) prior dienogest treatment were analyzed. A mouse model of endometriosis was also used to evaluate the effects of YAP1 inhibition on progesterone resistance. PARTICIPANTS/MATERIALS, SETTING, METHODS Primary endometriotic and endometrial stromal cells treated with YAP1 inhibitor or miR-21 mimic/inhibitor were used for the in vitro studies including decidualization induction, chromatin immunoprecipitation (ChIP), and RNA immunoprecipitation. Tissue specimens and serum from human and mouse were used for immunohistochemistry staining, exosome isolation, and microRNA (miRNA) quantification, respectively. MAIN RESULTS AND THE ROLE OF CHANCE Herein, we report, by using ChIP-PCR and RNA-IP, that YAP1 inhibits progesterone receptor (PGR) expression through upregulation of miR-21-5p. Upregulation of miR-21-5p not only reduces PGR expression but also inhibits endometrial stromal cell decidualization. Indeed, levels of YAP1 and miR-21-5p are inversely correlated with the level of PGR in human endometrial samples. In contrast, knockdown of YAP1 or treatment with verteporfin (VP), a YAP1 inhibitor, reduces miR-21-5p expression, thus leading to an increase in PGR expression in ectopic endometriotic stromal cells. In the mouse model of endometriosis, treatment with VP increases PGR expression and enhances decidualization. More importantly, VP synergistically increases the treatment effect of progestin in causing the regression of endometriotic lesions and improves the decidualization capability of the endometrium. Interestingly, treatment with dienogest, a synthetic progestin, reduces YAP1 and miR-21-5p expression in human cells and in the mouse model of endometriosis. Patients who received dienogest treatment for 6 months show a significant decrease in serum extracellular vesicle-associated miR-21-5p level. LARGE SCALE DATA A public dataset (GSE51981) containing a large cohort of endometriotic tissues is available from the Gene Expression Omnibus (GEO). LIMITATIONS, REASONS FOR CAUTION A large cohort of clinical samples is needed to verify the current diagnostic value of miR-21-5p in future studies. WIDER IMPLICATIONS OF THE FINDINGS The reciprocal regulation of YAP1 and PGR suggests that combined YAP1 inhibitor and progestin may be a better therapeutic approach for treating endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Ministry of Science and Technology, Taiwan (MOST-111-2636-B-006-012, MOST-111-2314-B-006-075-MY3, and MOST-106-2320-B-006-072-MY3). The authors have no conflict of interest to disclose.

Yes Associated Transcriptional Regulator 1 (YAP1) and WW Domain Containing Transcription Regulator (WWTR1) are required for murine pregnancy initiation

“…In addition to the cyclical presence of YAP1 as well as activation of the Hippo signaling pathway, the function of this pathway has also been associated with hormonal action. In disease states like breast cancer and endometriosis, YAP1 bound to TEAD transcription factors can induce transcription of ESR1, or alternatively, in endometriosis, YAP1 can regulate upstream factors that influence PGR expression (15,16). These reports support an indirect method of…”

“…In addition to the cyclical presence of Yap1 as well as activation of the Hippo signaling pathway, the function of this pathway has also been associated with hormonal action. In particular, in disease states like breast cancer and endometriosis, YAP1 bound to TEAD transcription factors can induce transcription of ESR1 or alternatively in endometriosis YAP1 can regulate upstream factors that influence PGR expression (16, 17). These reports support an indirect method of hormonal control and interpretation of signal, but it is possible within the scope of YAP1/WWTR1 function as transcriptional coactivators that they could play a direct role within hormone receptor function.…”

A Preliminary Investigation of the Roles of Endometrial Cells in Endometriosis Development via In Vitro and In Vivo Analyses

“…The first involves pooling individual endometrial-minced tissues from a donor dispersed into the peritoneal cavity of a recipient through intraperitoneal, which has demonstrated increased macrophage recruitment and production of inflammatory cytokines [104,105]. The second method, as indicated in the existing literature, frequently involves inducing endometriosis in mice through direct suturing of organized endometrial fragments or artificially decidualized endometrial tissue into the peritoneal cavity or peritoneum [106][107][108]. Numerous rodent and non-human primate studies have established that endometrial tissue fragments and non-dissociated epithelia, stroma, and glands can initiate endometriosis, which resembles the process of retrograde menstruation [109][110][111].…”

MicroRNAs in Endometriosis: Insights into Inflammation and Progesterone Resistance

“…Furthermore, miR-21-5p and Hippo/yes-associated protein 1 (YAP1) signaling pathway were upregulated, while the expression of PR was downregulated in endometriosis. Treatments with verteporfin (VP) and dienogest have been shown to downregulate miR-21-5p and YAP1 expression, leading to upregulation of PR expression, thus improving progesterone resistance in endometriosis in humans and mouse models [98].…”