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- Title
USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells.
- Authors
Liao, Yuning; Shao, Zhenlong; Liu, Yuan; Xia, Xiaohong; Deng, Yuanfei; Yu, Cuifu; Sun, Wenshuang; Kong, Weiyao; He, Xiaoyue; Liu, Fang; Guo, Zhiqiang; Chen, Guoxing; Tang, Daolin; Gan, Huoye; Liu, Jinbao; Huang, Hongbiao
- Abstract
Background: Hepatocellular carcinoma (HCC) remains a medical challenge due to its high proliferation and metastasis. Although deubiquitinating enzymes (DUBs) play a key role in regulating protein degradation, their pathological roles in HCC have not been fully elucidated. Methods: By using biomass spectrometry, co-immunoprecipitation, western blotting and immunofluorescence assays, we identify ribosomal protein S16 (RPS16) as a key substrate of ubiquitin-specific peptidase 1 (USP1). The role of USP1-RPS16 axis in the progression of HCC was evaluated in cell cultures, in xenograft mouse models, and in clinical observations. Results: We show that USP1 interacts with RPS16. The depletion of USP1 increases the level of K48-linked ubiquitinated-RPS16, leading to proteasome-dependent RPS16 degradation. In contrast, overexpression of USP1-WT instead of USP1-C90A (DUB inactivation mutant) reduces the level of K48-linked ubiquitinated RPS16, thereby stabilizing RPS16. Consequently, USP1 depletion mimics RPS16 deficiency with respect to the inhibition of growth and metastasis, whereas transfection-enforced re-expression of RPS16 restores oncogenic-like activity in USP1-deficient HCC cells. Importantly, the high expression of USP1 and RPS16 in liver tissue is a prognostic factor for poor survival of HCC patients. Conclusions: These findings reveal a previously unrecognized role for the activation of USP1-RPS16 pathway in driving HCC, which may be further developed as a novel strategy for cancer treatment.
- Subjects
PROTEIN stability; HEPATOCELLULAR carcinoma; PROGNOSIS; HUMAN growth; LABORATORY mice
- Publication
Journal of Experimental & Clinical Cancer Research (17569966), 2021, Vol 40, Issue 1, p1
- ISSN
1756-9966
- Publication type
Article
- DOI
10.1186/s13046-021-02008-3