Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice

作者全名："Lin, Xiao-Tong; Zhang, Jie; Liu, Ze-Yu; Wu, Di; Fang, Lei; Li, Chun-Ming; Yu, Hong-Qiang; Xie, Chuan-Ming"

作者地址："[Lin, Xiao-Tong; Zhang, Jie; Liu, Ze-Yu; Wu, Di; Fang, Lei; Yu, Hong-Qiang; Xie, Chuan-Ming] Army Med Univ, Mil Med Univ 3, Southwest Hosp, Inst Hepatobiliary Surg,Key Lab Hepatobiliary & Pa, Chongqing 400038, Peoples R China; [Li, Chun-Ming] Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 2, Chongqing 400010, Peoples R China"

通信作者："Xie, CM (通讯作者)，Army Med Univ, Mil Med Univ 3, Southwest Hosp, Inst Hepatobiliary Surg,Key Lab Hepatobiliary & Pa, Chongqing 400038, Peoples R China."

来源：CELL REPORTS

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001042724900001

JCR分区：Q1

影响因子：7.5

年份：2023

卷号：42

期号：7

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men, but the underlying mechanism remains to be further explored. Here, we report that ubiquitinated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is responsible for HCC tumorigenesis in males. Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation. Activated GAPDH interacts with TRAF2, leading to upregu-lation of the canonical and noncanonical NF-KB pathways, and increases PD-L1 and AR-VRK2 expression, followed by induction of immune evasion, HCC tumorigenesis, and metastasis. Notably, the GAPDH inhibitor koningic acid (KA) activates immune response and protects against FBXW10-driven HCC in vivo. In HCC clin-ical samples, the expression of active GAPDH is positively correlated with that of FBXW10 and VRK2. We pro-pose that the FBXW10/AR/VRK2/GAPDH/NF-KB axis is critical for HCC tumorigenesis in males. Targeting this axis with KA is a potential therapeutic strategy for male HCC patients."

基金机构：National Natural Science Foundation of China (NSFC) [32071294]; Army Medical University [2019XQY10]

基金资助正文："Acknowledgments This work was supported by the National Natural Science Foundation of China (NSFC) (32071294) and a direct grant from the Army Medical University (2019XQY10) to C.-M.X. We would like to thank Yan Jiang, Yujun Zhang, Jie- juan Lai, Ping Zheng, and Ling Shuai for collection of tissues and clinical infor- mation for each patient."