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Targeting hypoxia‐mediated YAP1 nuclear translocation ameliorates pathogenesis of endometriosis without compromising maternal fertility
Author(s) -
Lin ShihChieh,
Lee HsiuChi,
Hou PeiChi,
Fu JhaoLin,
Wu MengHsing,
Tsai ShawJenq
Publication year - 2017
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4922
Subject(s) - yap1 , endometriosis , hypoxia (environmental) , cancer research , biology , gene knockdown , pathogenesis , medicine , immunology , gene , chemistry , transcription factor , genetics , organic chemistry , oxygen
Endometriosis is a highly prevalent gynaecological 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 were up‐regulated by hypoxia via down‐regulation of LATS1, a kinase that inactivates YAP1. Disruption of hypoxia‐induced YAP1 signalling 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. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.