Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, People's Republic of China.
Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Cancer Sci. 2024 Sep;115(9):2998-3012. doi: 10.1111/cas.16290. Epub 2024 Jul 16.
In our previous study, we found that small ubiquitin-related modifier (SUMO)-activating enzyme ubiquitin-associated-2 domain (UBA2) was upregulated in hepatocellular carcinoma (HCC) patients who were insensitive to chemoembolization. In this study, we aimed to investigate the role of UBA2 in HCC progression. Three cohorts were used to evaluate the efficacy of UBA2 as a prognostic factor for HCC. Our results indicated that UBA2 was associated with aggressive clinical behaviors and was a strong indicator of poor prognosis in HCC. In vitro experiments demonstrated that UBA2 accelerated cell growth, invasion, and migration. These results were further supported by in vivo experiments. RNA-sequencing analysis indicated NQO1 as a target of UBA2, with its levels altering following UBA2 manipulation. The results were verified by western blotting (WB) and quantitative PCR. The SUMOplot Analysis Program predicted lysine residue K240 as a modification target of UBA2, which was confirmed by immunoprecipitation (IP) assays. Subsequent mutation of NQO1 at K240 in HCC cell lines and functional assays revealed the significance of this modification. In addition, the oncogenic effect of UBA2 could be reversed by the SUMO inhibitor ML792 in vivo and in vitro. In conclusion, our study elucidated the regulatory mechanism of UBA2 in HCC and suggested that the SUMO inhibitor ML792 may be an effective combinatory treatment for patients with aberrant UBA2 expression.
在我们之前的研究中，我们发现小泛素相关修饰酶（SUMO）激活酶泛素相关-2 结构域（UBA2）在对化疗栓塞不敏感的肝癌（HCC）患者中上调。在这项研究中，我们旨在研究 UBA2 在 HCC 进展中的作用。我们使用三个队列评估 UBA2 作为 HCC 预后因素的疗效。我们的结果表明，UBA2 与侵袭性临床行为相关，是 HCC 预后不良的强烈指标。体外实验表明 UBA2 加速了细胞生长、侵袭和迁移。体内实验进一步支持了这些结果。RNA 测序分析表明 NQO1 是 UBA2 的靶标，其水平随 UBA2 操作而改变。Western blot（WB）和定量 PCR 验证了这一结果。SUMOplot 分析程序预测赖氨酸残基 K240 是 UBA2 的修饰靶标，免疫沉淀（IP）试验证实了这一点。随后在 HCC 细胞系中突变 NQO1 的 K240 并进行功能测定，揭示了这种修饰的重要性。此外，SUMO 抑制剂 ML792 在体内和体外均可逆转 UBA2 的致癌作用。总之，我们的研究阐明了 UBA2 在 HCC 中的调控机制，并表明 SUMO 抑制剂 ML792 可能是治疗异常 UBA2 表达患者的有效联合治疗方法。
