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

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, Cheng Wang

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Article numbere44948
JournalEMBO Reports
Volume20
Issue number3
DOIs
StatePublished - Mar 2019

Keywords

  • YAP1-LATS2 feedback loop
  • cellular senescence
  • the Hippo pathway
  • tissue homeostasis
  • tumorigenesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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    He, C., Lv, X., Huang, C., Hua, G., Ma, B., Chen, X., Angeletti, P. C., Dong, J., Zhou, J., Wang, Z., Rueda, B. R., Davis, J. S., & Wang, C. (2019). YAP1-LATS2 feedback loop dictates senescent or malignant cell fate to maintain tissue homeostasis. EMBO Reports, 20(3), [e44948]. https://doi.org/10.15252/embr.201744948