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

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ORIGINAL PAPER

Ubiquitin-specific protease 2a promotes hepatocellular carcinoma progression via deubiquitination and stabilization of RAB1A Bin Xiong 1 & Junwei Huang 1 & Yan Liu 2 & Min Zou 3 & Zhibo Zhao 1 & Jianping Gong 1 & Xiaoling Wu 3 & Chan Qiu 3 Accepted: 2 October 2020 # International Society for Cellular Oncology 2020

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. LCMS/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. Keywords Hepatocellular carcinoma . Deubiquitinase . USP2a . RAB1A

1 Introduction Primary liver cancer (PLC) is estimated to be the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide [1]. Hepatocellular carcinoma Bin Xiong and Junwei Huang contributed equally to this work. * Chan Qiu [email protected] 1

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

2

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

3

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

(HCC) is the main pathological subtype of PLC (> 80%), and represents a heavy medical burden [2]. Patients presenting with