期刊
EMBO REPORTS
卷 20, 期 3, 页码 -出版社
WILEY
DOI: 10.15252/embr.201744948
关键词
cellular senescence; the Hippo pathway; tissue homeostasis; tumorigenesis; YAP1-LATS2 feedback loop
资金
- National Cancer Institute/National Institute of Health [1R01CA197976, 1R01CA201500]
- Olson Center for Women's Health
- Fred & Pamela Buffett Cancer Center [Lb595]
- Colleen's Dream Foundation
- Marsha Rivkin Center for Ovarian Cancer Research (Barbara Learned Bridge Funding Award)
- CoBRE grant from the Nebraska Center for Cellular Signaling/the National Institute of General Medicine/the National Institute for Health [5P30GM106397]
- Department of Obstetrics and Gynecology, Massachusetts General Hospital
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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