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- Title
WWP2 drives the progression of gastric cancer by facilitating the ubiquitination and degradation of LATS1 protein.
- Authors
Zou, Jianping; Zhou, Ling; Le, Yi; Fang, Zhi; Zhong, Min; Nie, Fengting; Wei, Xianpin; Zhang, Xiaomei; Chen, Zhen; Cai, Lingling; Wang, Heng; Xiong, Jianping; Fang, Ziling; Xiang, Xiaojun
- Abstract
Background: Large tumor suppressor kinase 1 (LATS1), one of the predominant components of the Hippo pathway, has been characterized as a key player controlling the proliferation and invasion of cancer cells, including gastric cancer (GC) cells. However, the mechanism by which the functional stability of LATS1 is modulated has yet to be elucidated. Methods: Online prediction tools, immunohistochemistry and western blotting assays were used to explore the expression of WW domain-containing E3 ubiquitin ligase 2 (WWP2) in GC cells and tissues. Gain- and loss-of-function assays, as well as rescue experiments were performed to determine the role of the WWP2-LATS1 axis in cell proliferation and invasion. Additionally, the mechanisms involving WWP2 and LATS1 were assessed by coimmunoprecipitation (Co-IP), immunofluorescence, cycloheximide and in vivo ubiquitination assays. Results: Our results demonstrate a specific interaction between LATS1 and WWP2. WWP2 was markedly upregulated and correlated with disease progression and a poor prognosis in GC patients. Moreover, ectopic WWP2 expression facilitated the proliferation, migration and invasion of GC cells. Mechanistically, WWP2 interacts with LATS1, resulting in its ubiquitination and subsequent degradation, leading to increased transcriptional activity of YAP1. Importantly, LATS1 depletion abolished the suppressive effects of WWP2 knockdown on GC cells. Furthermore, WWP2 silencing attenuated tumor growth by regulating the Hippo-YAP1 pathway in vivo. Conclusions: Our results define the WWP2-LATS1 axis as a critical regulatory mechanism of the Hippo-YAP1 pathway that promotes GC development and progression. 4DACTQjHnAfUrjtSe4YKAZ Video Abstract
- Subjects
PROTEOLYSIS; STOMACH cancer; HIPPO signaling pathway; UBIQUITINATION; CANCER cell proliferation; CANCER invasiveness
- Publication
Cell Communication & Signaling, 2023, Vol 21, Issue 1, p1
- ISSN
1478-811X
- Publication type
Article
- DOI
10.1186/s12964-023-01050-2