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<p>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.</p>

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USP5 deubiquitinates and stabilizes IMPDH2, to promote hepatocellular carcinoma progression

  • 期刊论文

  • 发表日期：

    2025年3月31日

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  • Shuoyi Jiang,
  • Liyang Jiang,
  • Yingying Xu,
  • Yunju Ma,
  • Yiran Deng,
  • Can Jiao,
  • Min Yin,
  • Chao Qin,
  • Jiale Li,
  • Li Zhang,
  • She Chen

摘要

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.