Long Guo, Wang Dong, Tang Jianing, Hu Kuan, Zhou Ledu
Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Cancer Cell Int. 2024 Jul 7;24(1):238. doi: 10.1186/s12935-024-03370-w.
Ubiquitination was considered to be a crucial factor in intrahepatic cholangiocarcinoma (iCCA) development. Herein, we identified Ubiquitin-specific peptidase 8 (USP8) as a key regulator for promoting the tumorigenesis of iCCA cell via stabilizing OGT. USP8 was overexpressed in human tumor tissues and correlated with worse survival. Moreover, the mass spectrometry and co-immunoprecipitation analysis indicated that USP8 interacted with OGT. USP8 worked as a bona fide deubiquitylase of OGT. It stabilized OGT in a deubiquitylation activity-dependent manner. Meanwhile, DUB-IN3, the USP8 inhibitor, could also restrain the malignancy of intrahepatic cholangiocarcinoma. In addition, USP8 depletion promoted the response of iCCA to pemigatinib. In conclusion, our findings pointed to a previously undocumented catalytic role for USP8 as a deubiquitinating enzyme of OGT. The USP8-OGT axis could be a potential target for iCCA therapy.
泛素化被认为是肝内胆管癌（iCCA）发生发展的关键因素。在此，我们鉴定出泛素特异性蛋白酶8（USP8）是通过稳定OGT促进iCCA细胞肿瘤发生的关键调节因子。USP8在人类肿瘤组织中高表达，且与较差的生存率相关。此外，质谱分析和免疫共沉淀分析表明USP8与OGT相互作用。USP8作为OGT的真正去泛素化酶发挥作用。它以去泛素化活性依赖的方式稳定OGT。同时，USP8抑制剂DUB-IN3也可抑制肝内胆管癌的恶性程度。此外，USP8缺失增强了iCCA对培米替尼的反应。总之，我们的研究结果指出了USP8作为OGT去泛素化酶以前未被记录的催化作用。USP8-OGT轴可能是iCCA治疗的潜在靶点。
