USP22 mediates the multidrug resistance of hepatocellular carcinoma via the SIRT1/AKT/MRP1 signaling pathway.
Drug treatments for hepatocellular carcinoma (HCC) often fail because of multidrug resistance (MDR). The mechanisms of MDR are complex but cancer stem cells (CSCs), which are able to self-renew and differentiate, have recently been shown to be involved. The deubiquitinating enzyme ubiquitin-specific protease 22 (USP22) is a marker for CSCs. This study aimed to elucidate the role of USP22 in MDR of HCC and the underlying mechanisms. Using in vitro and in vivo assays, we found that modified USP22 levels were responsible for the altered drug-resistant phenotype of BEL7402 and BEL/FU cells. Downregulation of USP22 dramatically inhibited the expression of ABCC1 (encoding MRP1) but weakly influenced ABCB1 (encoding P-glycoprotein). Sirtuin 1 (SIRT1) was reported previously as a functional mediator of USP22 that could promote HCC cell proliferation and enhance resistance to chemotherapy. In this study, USP22 directly interacted with SIRT1 and positively regulated SIRT1 protein expression. Regulation of the expression of both USP22 and SIRT1 markedly affected the AKT pathway and MRP1 expression. Inhibition of the AKT pathway by its specific inhibitor LY294002 resulted in downregulation of MRP1. USP22 and MRP1 expression was detected in 168 clinical HCC samples by immunohistochemical staining, and a firm relationship between USP22 and MRP1 was identified. Together, these results indicate that USP22 could promote the MDR in HCC cells by activating the SIRT1/AKT/MRP1 pathway. USP22 might be a potential target, through which the MDR of HCC in clinical setting could be reversed.
['Ling|Sunbin|S|', 'Li|Jie|J|', 'Shan|Qiaonan|Q|', 'Dai|Haojiang|H|', 'Lu|Di|D|', 'Wen|Xue|X|', 'Song|Penghong|P|', 'Xie|Haiyang|H|', 'Zhou|Lin|L|', 'Liu|Jimin|J|', 'Xu|Xiao|X|', 'Zheng|Shusen|S|']
D018435:ATP Binding Cassette Transporter, Subfamily B D048868:Adaptor Proteins, Signal Transducing D000704:Analysis of Variance D000818:Animals D051017:Apoptosis Regulatory Proteins D006528:Carcinoma, Hepatocellular D045744:Cell Line, Tumor D002867:Chromones D004195:Disease Models, Animal D015536:Down-Regulation D018432:Drug Resistance, Multiple D019008:Drug Resistance, Neoplasm D004791:Enzyme Inhibitors D006801:Humans D008113:Liver Neoplasms D008297:Male D051379:Mice D008819:Mice, Nude D009025:Morpholines D027425:Multidrug Resistance-Associated Proteins D056564:Sirtuin 1 D013869:Thiolester Hydrolases D043222:Ubiquitin Thiolesterase D023041:Xenograft Model Antitumor Assays
USP22 multidrug resistance hepatocellular carcinoma SIRT1 MRP1