Yang Yingnan, Jia Siying, Zhu Ning, Xiao Xuelian, Ma Ying, Tu Kangsheng, Guo Yong, Xu Qiuran
The Second Clinical Medical College of Zhejiang Chinese Medical University, 310053, Hangzhou, China.
Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 310014, Hangzhou, China.
Biol Direct. 2024 Apr 24;19(1):31. doi: 10.1186/s13062-024-00475-0.
Deubiquitinating enzymes (DUBs) cleave ubiquitin on substrate molecules to maintain protein stability. DUBs reportedly participate in the tumorigenesis and tumour progression of hepatocellular carcinoma (HCC). OTU deubiquitinase 5 (OTUD5), a DUB family member, has been recognized as a critical regulator in bladder cancer, breast cancer and HCC. However, the expression and biological function of OTUD5 in HCC are still controversial.
We determined that the expression of OTUD5 was significantly upregulated in HCC tissues. High levels of OTUD5 were also detected in most HCC cell lines. TCGA data analysis demonstrated that high OTUD5 expression indicated poorer overall survival in HCC patients. OTUD5 silencing prominently suppressed HCC cell proliferation, while its overexpression markedly enhanced the proliferation of HCC cells. Mass spectrometry analysis revealed solute carrier family 38 member 1 (SLC38A1) as a candidate downstream target protein of OTUD5. Coimmunoprecipitation analysis confirmed the interaction between OTUD5 and SLC38A1. OTUD5 knockdown reduced and OTUD5 overexpression increased SLC38A1 protein levels in HCC cells. However, OTUD5 alteration had no effect on SLC38A1 mRNA expression. OTUD5 maintained SLC38A1 stability by preventing its ubiquitin-mediated proteasomal degradation. SLC38A1 silencing prominently attenuated the OTUD5-induced increase in HCC cell proliferation. Finally, OTUD5 knockdown markedly suppressed the growth of HCC cells in vivo.
OTUD5 is an oncogene in HCC. OTUD5 contributes to HCC cell proliferation by deubiquitinating and stabilizing SLC38A1. These results may provide a theoretical basis for the development of new anti-HCC drugs.
去泛素化酶（DUBs）可切割底物分子上的泛素以维持蛋白质稳定性。据报道，DUBs参与肝细胞癌（HCC）的肿瘤发生和肿瘤进展。OTU去泛素酶5（OTUD5）是一种DUB家族成员，已被认为是膀胱癌、乳腺癌和HCC中的关键调节因子。然而，OTUD5在HCC中的表达及生物学功能仍存在争议。
我们确定OTUD5在HCC组织中的表达显著上调。在大多数HCC细胞系中也检测到高水平的OTUD5。TCGA数据分析表明，OTUD5高表达提示HCC患者的总生存期较差。OTUD5沉默显著抑制HCC细胞增殖，而其过表达则明显增强HCC细胞的增殖。质谱分析显示溶质载体家族38成员1（SLC38A1）是OTUD5的候选下游靶蛋白。免疫共沉淀分析证实了OTUD5与SLC38A1之间的相互作用。OTUD5敲低降低、OTUD5过表达增加HCC细胞中SLC38A1蛋白水平。然而，OTUD5改变对SLC38A1 mRNA表达无影响。OTUD5通过防止SLC38A1泛素介导的蛋白酶体降解来维持其稳定性。SLC38A1沉默显著减弱OTUD5诱导的HCC细胞增殖增加。最后，OTUD5敲低显著抑制体内HCC细胞的生长。
OTUD5是HCC中的一种癌基因。OTUD5通过去泛素化和稳定SLC38A1促进HCC细胞增殖。这些结果可能为开发新的抗HCC药物提供理论依据。
