Targeting hypoxia ‐mediated YAP1 nuclear translocation ameliorates pathogenesis of endometriosis without compromising maternal fertility

Abstract Endometriosis is a highly prevalent gynecological disease that severely reduces women's health and quality of life. Ectopic endometriotic lesions have evolved mechanisms to survive in the hypoxic peritoneal microenvironment by regulating the expression of a significant subset of genes. However, the master regulator controlling these genes remains to be characterized. Herein, by using bioinformatics analysis and experimental verification, we identified Yes‐Associated Protein 1 (YAP1) as a master regulator of endometriosis. Nuclear localization and transcriptional activity of YAP1 was upregulated by hypoxia via downregulation of LATS1, a kinase that inactivates YAP1. Disruption of hypoxia‐induced YAP1 signaling by siRNA knockdown or inhibitor treatment abolished critical biological processes involved in endometriosis development such as steroidogenesis, angiogenesis, inflammation, migration, innervation, and cell proliferation. Treatment with a YAP1 inhibitor caused the regression of endometriotic lesions without affecting maternal fertility or the growth rate of offspring in the mouse model of endometriosis. Taken together, we identify hypoxia/LATS1/YAP1 as a novel pathway for the pathogenesis of endometriosis and demonstrate that targeting YAP1 might be an alternative approach to treat endometriosis.
Source: The Journal of Pathology - Category: Pathology Authors: Tags: Original Paper Source Type: research