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."
ESI学科分类：MOLECULAR BIOLOGY & GENETICS
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) ; 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."