Du Dongnian, Zhang Wenming, Zhang Dandan, Liu Lingpeng, Li Jiajuan, Chen Zehao, Yu Xuzhe, Ye Miao, Wang Wei, Li Zijing, Shao Jianghua
Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China.
Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China.
Cell Death Dis. 2025 Mar 31;16(1):228. doi: 10.1038/s41419-025-07567-3.
Negative regulator of ubiquitin-like protein 1 (NUB1), an inhibitor of neural precursor cells expressed developmentally downregulated 8 (NEDD8), is implicated in tumor growth. However, the expression of NUB1 in hepatocellular carcinoma (HCC) and its effects on HCC growth remain unclear. In this study, our findings revealed reduced NUB1 protein expression in HCC tissues and cells, leading to increased proliferating cell nuclear antigen (PCNA) protein stability through upregulating NEDD8 to promote HCC cell growth. Mechanistically, NUB1 reduction upregulated NEDD8 to promote PCNA NEDDylation at lysine 164 (Lys164), in turn, antagonized PCNA K48-linked polyubiquitination, thereby increasing the stability of PCNA in HCC cells. Finally, the results of the in vitro and in vivo experiments revealed that the NEDDylation inhibitor TAS4464 could inhibit PCNA NEDDylation to decrease PCNA protein expression, thereby suppressing HCC cell growth. Collectively, our results identified NUB1 as a negative regulator of HCC proliferation and confirmed that PCNA NEDDylation promotes PCNA protein stability by antagonizing PCNA polyubiquitination. This study provides a new perspective on the specific mechanism of HCC growth. It expands our understanding of the role of NEDDylation in the regulation of substrate proteins and their functions.
泛素样蛋白1负调节因子（NUB1）是神经前体细胞表达的发育性下调蛋白8（NEDD8）的抑制剂，与肿瘤生长有关。然而，NUB1在肝细胞癌（HCC）中的表达及其对HCC生长的影响仍不清楚。在本研究中，我们的发现揭示了HCC组织和细胞中NUB1蛋白表达降低，通过上调NEDD8导致增殖细胞核抗原（PCNA）蛋白稳定性增加，从而促进HCC细胞生长。机制上，NUB1表达降低上调NEDD8，促进PCNA在赖氨酸164（Lys164）位点的NEDD化，进而拮抗PCNA的K48连接的多聚泛素化，从而增加HCC细胞中PCNA的稳定性。最后，体外和体内实验结果表明，NEDD化抑制剂TAS4464可抑制PCNA的NEDD化以降低PCNA蛋白表达，从而抑制HCC细胞生长。总的来说，我们的结果确定NUB1是HCC增殖的负调节因子，并证实PCNA的NEDD化通过拮抗PCNA的多聚泛素化促进PCNA蛋白稳定性。本研究为HCC生长的具体机制提供了新的视角。它扩展了我们对NEDD化在调节底物蛋白及其功能中的作用的理解。
