Ubiquitin-specific protease 1 facilitates hepatocellular carcinoma progression by modulating mitochondrial fission and metabolic reprogramming via cyclin-dependent kinase 5 stabilization.

Autor: Bian S; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.; Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China., Ni W; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China., Zhou L; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.; Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China., Tong Y; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.; Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China., Dai C; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.; Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China., Zhao X; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China., Qiang Y; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.; Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China., Gao J; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.; Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China., Xiao Y; Department of Interventional Radiology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China., Liu W; School of Life Sciences, Nantong Laboratory of Development and Diseases, Nantong University, Nantong, China., Chen C; School of Life Sciences, Nantong Laboratory of Development and Diseases, Nantong University, Nantong, China., Lin S; Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China.; Fudan Zhangjiang Institute, Shanghai, China., Gong J; Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, Shanghai, China.; Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China., Zhao S; Department of Interventional Radiology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China., Chen Y; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China., Lin Z; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China., Liu D; School of Life Sciences, Nantong Laboratory of Development and Diseases, Nantong University, Nantong, China. liudongtom@gmail.com., Zhao H; Department of Interventional Radiology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China. zhaohui800@163.com., Zheng W; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China. wenjiezheng@ntu.edu.cn.; Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China. wenjiezheng@ntu.edu.cn.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2024 Sep; Vol. 31 (9), pp. 1202-1218. Date of Electronic Publication: 2024 Jul 15.
DOI: 10.1038/s41418-024-01342-1
Abstrakt: Although deubiquitinases (DUBs) have been well described in liver tumorigenesis, their potential roles and mechanisms have not been fully understood. In this study, we identified ubiquitin-specific protease 1 (USP1) as an oncogene with essential roles during hepatocellular carcinoma (HCC) progression. USP1, with elevated expression levels and clinical significance, was identified as a hub DUB for HCC in multiple bioinformatics datasets. Functionally, USP1 overexpression significantly enhanced the malignant behaviors in HCC cell lines and spheroids in vitro, as well as the zebrafish model and the xenograft model in vivo. In contrast, genetic ablation or pharmacological inhibition of USP1 dramatically impaired the phenotypes of HCC cells. Specifically, ectopic USP1 enhanced aggressive properties and metabolic reprogramming of HCC cells by modulating mitochondrial dynamics. Mechanistically, USP1 induced mitochondrial fission by enhancing phosphorylation of Drp1 at Ser616 via deubiquitination and stabilization of cyclin-dependent kinase 5 (CDK5), which could be degraded by the E3 ligase NEDD4L. The USP1/CDK5 modulatory axis was activated in HCC tissues, which was correlated with poor prognosis of HCC patients. Furthermore, Prasugrel was identified as a candidate USP1 inhibitor for targeting the phenotypes of HCC by an extensive computational study combined with experimental validations. Taken together, USP1 induced malignant phenotypes and metabolic reprogramming by modulating mitochondrial dynamics in a CDK5-mediated Drp1 phosphorylation manner, thereby deteriorating HCC progression.
(© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)
Databáze: MEDLINE
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