Targeting YAP1 ameliorates progesterone resistance in endometriosis

• Published in: Human reproduction (Oxford) 2023-06, Vol.38 (6), p.1124-1134
• Main Authors: Lin, Shih-Chieh, Li, Wan-Ning, Lin, Shin-Chih, Hou, Haun-Tzu, Tsai, Ya-Chuan, Lin, Tin-Chien, Wu, Meng-Hsing, Tsai, Shaw-Jenq
• Format: Article
• Language: English
• Subjects: Animals; Endometriosis - pathology; Endometrium - metabolism; Female; Humans; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Pregnancy; Progesterone - metabolism; Progestins - therapeutic use; Stromal Cells - metabolism; Transcription Factors - metabolism
• ISSN: 0268-1161; 1460-2350
• DOI: 10.1093/humrep/dead071

Does YAP1 inhibition alleviate progesterone resistance in endometriosis? YAP1 inhibition reduces progesterone resistance in vitro and in vivo. 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. 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. 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. 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. A public dataset (GSE51981) containing a large cohort of endometriotic tiss