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USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells
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 s...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215741/ https://www.ncbi.nlm.nih.gov/pubmed/34154657 http://dx.doi.org/10.1186/s13046-021-02008-3 |
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author | 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 |
author_facet | 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 |
author_sort | Liao, Yuning |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-02008-3. |
format | Online Article Text |
id | pubmed-8215741 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-82157412021-06-23 USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells 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 J Exp Clin Cancer Res Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-02008-3. BioMed Central 2021-06-21 /pmc/articles/PMC8215741/ /pubmed/34154657 http://dx.doi.org/10.1186/s13046-021-02008-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research 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 USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells |
title | USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells |
title_full | USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells |
title_fullStr | USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells |
title_full_unstemmed | USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells |
title_short | USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells |
title_sort | usp1-dependent rps16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215741/ https://www.ncbi.nlm.nih.gov/pubmed/34154657 http://dx.doi.org/10.1186/s13046-021-02008-3 |
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