Abstract
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.
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All data generated or analyzed during this study are included in this published article. All of the data and material in this study are available when requested.
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Funding
This study was supported by grants from National Natural Science Foundation (82070622, 82272839, 81702419), the Key Research and Development Plan of Jiangsu Province (BE2020668), Shanghai Natural Science Foundation (23ZR1445500), Jiangsu Health Innovation Team Program (CX2023001), Jiangsu Province Capability Improvement Project through Science, Technology and Education (ZDXK202234), Jiangsu Provincial Research Hospital (YJXYY202204), Nantong Health Commission Project (QN2022002).
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Wenjie Zheng, Hui Zhao, and Dong Liu designed and supervised this study. Saiyan Bian, Wenkai Ni, and Linlin Zhou drafted of the manuscript. Saiyan Bian, Yun Tong, Wei Liu, Chengchen Dai, Xuying Zhao, Yuwei Qiang, Jie Gao conducted the experiments. Yifu Xiao, Shengli Lin, and Suming Zhao collected clinical samples and performed the statistics. Jianing Gong performed the structure-based drug screening. Yinqi Chen and Zhaoyi Lin made grammar revision. All authors read and approved the final version of the manuscript.
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This study was approved by the ethical committee of Nantong University Affiliated Hospital and the Animal Care and Use Committee of Nantong University.
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Bian, S., Ni, W., Zhou, L. et al. Ubiquitin-specific protease 1 facilitates hepatocellular carcinoma progression by modulating mitochondrial fission and metabolic reprogramming via cyclin-dependent kinase 5 stabilization. Cell Death Differ 31, 1202–1218 (2024). https://doi.org/10.1038/s41418-024-01342-1
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DOI: https://doi.org/10.1038/s41418-024-01342-1
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