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

Authors

Chunbo He, Massachusetts General Hospital & Huazhong Agricultural University & University of Nebraska Medical Center
Xiangmin Lv, Massachusetts General Hospital & University of Nebraska Medical Center
Cong Huang, Massachusetts General Hospital & University of Nebraska Medical Center
Guohua Hua, Huazhong Agricultural University
Bowen Ma, University of Nebraska Medical Center
Xingcheng Chen, University of Nebraska Medical Center
Peter C. Angeletti, University of Nebraska-LincolnFollow
Jixin Dong, University of Nebraska Medical Center
Jin Zhou, Huazhong Agricultural University & The Eighth Affiliated Hospital of Sun Yat-Sen University
Zhengfeng Wang, Huazhong Agricultural University & The First Affiliated Hospital of Zhengzhou University
Bo R. Rueda, Massachusetts General Hospital
John S. Davis, University of Nebraska Medical Center & Omaha Veterans Affairs Medical Center
Cheng Wang, Massachusetts General Hospital & University of Nebraska Medical CenterFollow

ORCID IDs

https://orcid.org/0000-0002-0911-8254

Date of this Version

2-12-2019

Citation

U.S. Government Work

Comments

YAP1-LATS2 feedback loop dictates cell fate Chunbo He et al 10.15252/embr.201744948

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.