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USP5 deubiquitinates and stabilizes IMPDH2, to promote hepatocellular carcinoma progression

Oncogene volume 44, pages 1936–1948 (2025)Cite this article

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Abstract

Modulating deubiquitinase activity is an emerging therapeutic approach for cancer. In this study, ubiquitin-specific protease 5 (USP5), a deubiquitinase, was found to be frequently overexpressed in hepatocellular carcinoma (HCC) and associated with poor prognosis in patients with HCC. Inosine monophosphate dehydrogenase 2 (IMPDH2) was identified as a binding partner of USP5. USP5 N-terminal ___domain (cryptic ZnF-UBP and ZnF-UBP ___domain) interacted with IMPDH2 (251-514 aa). IMPDH2 positively correlated with USP5 expression in HCC. Mechanistically, USP5 removed Lys48-linked ubiquitin chains from IMPDH2 through its deubiquitinase activity, preventing its ubiquitin-mediated degradation and stabilizing IMPDH2. The USP5-IMPDH2 axis promoted HCC proliferation, and metastasis mediated by epithelial-mesenchymal transition (EMT) process in HCC cells and Huh7 xenograft tumors in zebrafish. Notably, GTP biosynthesis pathway was involved in HCC progression induced by USP5. Furthermore, administration of WP1130, a USP5 inhibitor, or IMPDH2 reduction by shRNA facilitated the tumor-suppressive role of sorafenib in HCC cells and Huh7 xenograft tumors in nude mice. Together, we identified IMPDH2 as a substrate of USP5, which participates in USP5 induced promotion of HCC progression. Targeting the USP5-IMPDH2 axis might offer potential therapeutic benefits for patients with HCC.

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Fig. 1: USP5 N-terminal ___domain interacts with IMPDH2 C-terminal catalytic ___domain.
Fig. 2: IMPDH2 promotes the proliferation and metastasis of HCC.
Fig. 3: IMPDH2 knockdown reverses USP5 induced HCC proliferation.
Fig. 4: IMPDH2 knockdown reverses USP5 induced HCC metastasis.
Fig. 5: USP5 deubiquitinates Lys48-linked ubiquitin chain of IMPDH2 and stabilizes IMPDH2 protein.
Fig. 6: GTP participates in USP5 promoted HCC proliferation and metastasis.
Fig. 7: WP1130, a USP5 inhibitor, enhances the anti‑tumor effect of sorafenib.

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All data that support the findings are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC) (82173308) and the Natural Science Foundation of Shanghai (#23ZR1412600).

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Author notes

  1. These authors contributed equally: Shuoyi Jiang, Liyang Jiang, Yingying Xu.

Authors and Affiliations

  1. NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 130 Dong’an Road, Xuhui District, Shanghai, 200032, China

    Shuoyi Jiang, Yingying Xu, Yiran Deng, Can Jiao, Jiale Li, Li Zhang & She Chen

  2. Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215006, Jiangsu, China

    Liyang Jiang

  3. Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, 215000, Jiangsu, China

    Liyang Jiang

  4. National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China

    Yunju Ma

  5. Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Min Yin & Chao Qin

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Contributions

SC and YX designed and conceived this project. SJ, LJ and YM performed experiments and generated data. SJ, YD, CJ, MY, CQ and JL analyzed data. LZ provided technical and management support. SJ wrote the draft. SC and YX revised and finalized the manuscript. All authors contributed to and approved the manuscript.

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Correspondence to She Chen.

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The authors declare no competing interests.

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The informed consent was obtained from patients and the study was approved by the research ethics committee of Zhongshan Hospital. All the animal procedures were performed according to the criteria outlined in the “Guide for the Care and Use of Laboratory Animals” prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 86-23 revised 1985). Studies were approved by the Shanghai Medical Experimental Animal Care Commission.

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Jiang, S., Jiang, L., Xu, Y. et al. USP5 deubiquitinates and stabilizes IMPDH2, to promote hepatocellular carcinoma progression. Oncogene 44, 1936–1948 (2025). https://doi.org/10.1038/s41388-025-03355-7

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