PUBLICATION
USP5 deubiquitinates and stabilizes IMPDH2, to promote hepatocellular carcinoma progression
- Authors
- Jiang, S., Jiang, L., Xu, Y., Ma, Y., Deng, Y., Jiao, C., Yin, M., Qin, C., Li, J., Zhang, L., Chen, S.
- ID
- ZDB-PUB-250401-28
- Date
- 2025
- Source
- Oncogene : (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Carcinoma, Hepatocellular*/genetics
- Carcinoma, Hepatocellular*/metabolism
- Carcinoma, Hepatocellular*/pathology
- Cell Line, Tumor
- Cell Proliferation
- Disease Progression
- Epithelial-Mesenchymal Transition/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- IMP Dehydrogenase*/genetics
- IMP Dehydrogenase*/metabolism
- Liver Neoplasms*/genetics
- Liver Neoplasms*/metabolism
- Liver Neoplasms*/pathology
- Male
- Mice
- Mice, Nude
- Ubiquitin-Specific Proteases*/genetics
- Ubiquitin-Specific Proteases*/metabolism
- Ubiquitination
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 40164869 Full text @ Oncogene
Citation
Jiang, S., Jiang, L., Xu, Y., Ma, Y., Deng, Y., Jiao, C., Yin, M., Qin, C., Li, J., Zhang, L., Chen, S. (2025) USP5 deubiquitinates and stabilizes IMPDH2, to promote hepatocellular carcinoma progression. Oncogene. :.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping