Cellular gp96 upregulates AFP expression by blocking NR5A2 SUMOylation and ubiquitination in hepatocellular carcinoma  

作　　者：Liyuan Qian Zhentao Liang Zihao Wang Jiuru Wang Xin Li Jingmin Zhao Zihai Li Lizhao Chen Yongai Liu Ying Ju Changfei Li Songdong Meng 

机构地区：[1]Key Laboratory of Pathogen Microbiology and Immunology,Institute of Microbiology,Chinese Academy of Sciences,Beijing 100101,China [2]University of Chinese Academy of Science,Beijing 100049,China [3]Department of Pathology and Hepatology,The Fifth Medical Centre,Chinese PLA General Hospital,Beijing 100039,China [4]Pelotonia Institute for Immuno-Oncology,The Ohio State University Comprehensive Cancer Center—The James,Columbus,OH 43210,USA

出　　处：《Journal of Molecular Cell Biology》2023年第5期66-79,共14页分子细胞生物学报（英文版）

基　　金：supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29040000);the Industrial Innovation Team grant from Foshan Industrial Technology Research Institute,Chinese Academy of Sciences,the National Natural Science Foundation of China(32070163,81871297,and 81903142);China ATOMIC Energy Authority,Foshan High-level Hospital Construction DengFeng Plan,and Guangdong Province Biomedical Innovation Platform Construction Project Tumor Immunobiotherapy.

摘　　要：Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, asubstantial proportion of HCC patients have either normal or marginally increased AFP levels in serum, and the underlyingmechanisms are not fully understood. In the present study, we provided in vitro and in vivo evidence that heat shock protein gp96promoted AFP expression at the transcriptional level in HCC. NR5A2 was identified as a key transcription factor for the AFP gene, andits stability was enhanced by gp96. A further mechanistic study by co-immunoprecipitation, GST pull-down, and molecular dockingshowed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539. Thebinding of gp96 inhibited SUMOylation, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCCpatients indicated that gp96 expression in tumors was positively correlated with serum AFP levels. Therefore, our study uncovered anovel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and ubiquitination.These findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.

关 键 词：GP96 AFP NR5A2 RanBP2 SUMOYLATION 

分 类 号：R735.7[医药卫生—肿瘤]