YAP1‐LATS2 feedback loop dictates senescent or malignant cell fate to maintain tissue homeostasis release_n3f5horrk5befkvwi5n5bgsm44

by Chunbo He, Xiangmin Lv, Cong Huang, Guohua Hua, Bowen Ma, Xingcheng Chen, Peter C Angeletti, Jixin Dong, Jin Zhou, Zhengfeng Wang, Bo R Rueda, John S Davis (+1 others)

Published in EMBO Reports by EMBO.

2019   Volume 20, Issue 3, e44948

Abstract

Dysfunction of the homeostasis-maintaining systems in specific cell types or tissues renders the organism susceptible to a range of diseases, including cancers. One of the emerging mechanisms for maintaining tissue homeostasis is cellular senescence. Here, we report that the Hippo pathway plays a critical role in controlling the fate of ovarian cells. Hyperactivation of Yes-associated protein 1 (YAP1), the major effector of the Hippo pathway, induces senescence in cultured primary human ovarian surface epithelial cells (hOSEs). Large tumor suppressor 2 (LATS2), the primary upstream negative regulator of YAP1, is elevated in both YAP1-induced and natural replicative-triggered senescence. Deletion of LATS2 in hOSEs prevents these cells from natural replicative and YAP1-induced senescence. Most importantly, loss of LATS2 switches ovarian cells from YAP-induced senescence to malignant transformation. Our results demonstrate that LATS2 and YAP1, two major components of the Hippo/YAP signaling pathway, form a negative feedback loop to control YAP1 activity and prevent ovarian cells from malignant transformation. Human cancer genomic data extracted from TCGA datasets further confirm the clinical relevance of our finding.
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Date   2019-02-12
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