USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells
Open Access
- 21 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Experimental & Clinical Cancer Research
- Vol. 40 (1), 1-16
- https://doi.org/10.1186/s13046-021-02008-3
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.Keywords
Funding Information
- National Natural Science Foundation of China (82002481, 82072810, 81972399)
- the open research funds from the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital (202011-204, 202011-304)
- Natural Science Foundation research team of Guangdong Province (2018B030312001)
- The Science and Technology Program of Guangzhou (202002030107)
- projects from Foundation for Higher Education of Guangdong (2019KQNCX113)
- Special fund of Foshan Summit plan (2019D001)
- Grant from Foshan Science technology and Medical foundation (1920001000958)
This publication has 48 references indexed in Scilit:
- Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradationNature Communications, 2017
- Proteasome-associated deubiquitinase ubiquitin-specific protease 14 regulates prostate cancer proliferation by deubiquitinating and stabilizing androgen receptorCell Death & Disease, 2017
- Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitinationThe Journal of Experimental Medicine, 2016
- Twist1 promotes breast cancer invasion and metastasis by silencing Foxa1 expressionOncogene, 2016
- USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistanceNeuro-Oncology, 2015
- IKKβ phosphorylation regulates RPS3 nuclear translocation and NF-κB function during infection with Escherichia coli strain O157:H7Nature Immunology, 2011
- USP10 Regulates p53 Localization and Stability by Deubiquitinating p53Cell, 2010
- Cancer Metastasis Is Accelerated through Immunosuppression during Snail-Induced EMT of Cancer CellsCancer Cell, 2009
- The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expressionNature, 2000
- The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cellsNature, 2000