O-GlcNAcylation of E3 ubiquitin ligase SKP2 promotes hepatocellular carcinoma proliferation

作者全名："Feng, Zhongqi; Yin, Jiaxin; Zhang, Zhirong; Chen, Zhen; Huang, Luyi; Tang, Ni; Wang, Kai"

作者地址："[Feng, Zhongqi; Yin, Jiaxin; Zhang, Zhirong; Chen, Zhen; Huang, Luyi; Tang, Ni; Wang, Kai] Chongqing Med Univ, Affiliated Hosp 2, Dept Infect Dis, Key Lab Mol Biol Dis,Minist Educ,Inst Viral Hepati, Chongqing 400016, Peoples R China"

通信作者："Huang, LY; Tang, N; Wang, K (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Infect Dis, Key Lab Mol Biol Dis,Minist Educ,Inst Viral Hepati, Chongqing 400016, Peoples R China."

来源：ONCOGENE

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001175029500005

JCR分区：Q1

影响因子：8

年份：2024

卷号：43

期号：15

开始页：1149

结束页：1159

文献类型：Article

关键词：　

摘要："O-linked-beta-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) and ubiquitination are critical posttranslational modifications that regulate tumor development and progression. The continuous progression of the cell cycle is the fundamental cause of tumor proliferation. S-phase kinase-associated protein 2 (SKP2), an important E3 ubiquitin ligase, assumes a pivotal function in the regulation of the cell cycle. However, it is still unclear whether SKP2 is an effector of O-GlcNAcylation that affects tumor progression. In this study, we found that SKP2 interacted with O-GlcNAc transferase (OGT) and was highly O-GlcNAcylated in hepatocellular carcinoma (HCC). Mechanistically, the O-GlcNAcylation at Ser34 stabilized SKP2 by reducing its ubiquitination and degradation mediated by APC-CDH1. Moreover, the O-GlcNAcylation of SKP2 enhanced its binding ability with SKP1, thereby enhancing its ubiquitin ligase function. Consequently, SKP2 facilitated the transition from the G1-S phase of the cell cycle by promoting the ubiquitin degradation of cell cycle-dependent kinase inhibitors p27 and p21. Additionally, targeting the O-GlcNAcylation of SKP2 significantly suppressed the proliferation of HCC. Altogether, our findings reveal that O-GlcNAcylation, a novel posttranslational modification of SKP2, plays a crucial role in promoting HCC proliferation, and targeting the O-GlcNAcylation of SKP2 may become a new therapeutic strategy to impede the progression of HCC."

基金机构："National Natural Science Foundation of China (National Science Foundation of China) [82272975, 82073251, 82072286, 82304288]; China National Natural Science Foundation [2023YFC23068]; National Key Research and Development Program of China [2023DBXM007]; Innovative and Entrepreneurial Team of Chongqing Talents Plan, Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau) [W0036, W0101]; Future Medical Youth Innovation Team of Chongqing Medical University; Senior Medical Talents Program of Chongqing for Young and Middle-aged, and the Kuanren talents and DengFeng program of the second affiliated hospital of Chongqing Medical University"

基金资助正文："We are grateful that Prof. Tongchuan He (University of Chicago, USA) kindly provided the AdEasy system. We also thank Prof. Ding Xue (Tsinghua University, Beijing, China) for supplying the CRISPR/Cas9 system. This work was supported by the China National Natural Science Foundation (Grant nos. 82272975, 82073251, 82072286, 82304288), the National Key Research and Development Program of China (2023YFC23068), the Innovative and Entrepreneurial Team of Chongqing Talents Plan, Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2023DBXM007), the Future Medical Youth Innovation Team of Chongqing Medical University (W0036, W0101), Senior Medical Talents Program of Chongqing for Young and Middle-aged, and the Kuanren talents and DengFeng program of the second affiliated hospital of Chongqing Medical University."