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Ubiquitin-specific protease 2a promotes hepatocellular carcinoma progression via deubiquitination and stabilization of RAB1A

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Abstract

Purpose

Deubiquitination, the inverse process of ubiquitination, is catalyzed by deubiquitinases (DUBs) that remove ubiquitin from target proteins and subsequently prevent their degradation by proteasomes. Previously, deubiquitination has been found to be involved in hepatocellular carcinoma (HCC) progression. As yet, however, little is known about the exact role of deubiquitination in the development and/or progression of this type of cancer.

Methods

HCC tissues and tissue microarrays were used to detect expression of the DUB ubiquitin-specific protease 2a (USP2a). The critical role of USP2a in HCC development and progression was assessed in both in vitro cell and in vivo animal models. LC-MS/MS analyses were performed to identify potential targets of USP2a in HCC cells, after which regulation of target protein stability and ubiquitin status by USP2a were investigated.

Results

We found that USP2a was significantly upregulated in HCC tissues, and that a high expression was positively associated with a poor prognosis. Subsequently, we found that USP2a silencing resulted in inhibition of HCC cell proliferation, migration and invasion, whereas exogenous USP2a overexpression resulted in the opposite effects, both in vitro and in vivo. Mechanistically, LC-MS/MS analysis revealed that RAB1A, a key regulator of the ER and Golgi vesicular transport system, serves as a potential target of USP2a in HCC cells. In addition, we found that USP2a can deubiquitinate and stabilize RAB1A and prevent its degradation, and that this process is required for inducing HCC progression by USP2a.

Conclusions

Our data indicate that USP2a can promote HCC progression via deubiquitination and stabilization of RAB1A. This observation indicates that DUB targeting may serve as a novel approach to improve the treatment of HCC.

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Acknowledgements

This study was supported by the Natural Science Foundation of Chongqing (cstc2020jcyj-msxmX0214) and the Science & Technology Department of Sichuan Province (2018JY0276).

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Author notes

  1. Bin Xiong and Junwei Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China

    Bin Xiong, Junwei Huang, Zhibo Zhao & Jianping Gong

  2. Department of Gastroenterology, The Fifth people’s Hospital of Chengdu, Chengdu, Sichuan, 611130, People’s Republic of China

    Yan Liu

  3. Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China

    Min Zou, Xiaoling Wu & Chan Qiu

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  1. Bin Xiong
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Correspondence to Chan Qiu.

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Xiong, B., Huang, J., Liu, Y. et al. Ubiquitin-specific protease 2a promotes hepatocellular carcinoma progression via deubiquitination and stabilization of RAB1A. Cell Oncol. 44, 329–343 (2021). https://doi.org/10.1007/s13402-020-00568-8

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