O-GlcNAcylation of YTHDF2 promotes HBV-related hepatocellular carcinoma progression in an N^(6)-methyladenosine-dependent manner  

作　　者：Yang Yang Yu Yan Jiaxin Yin Ni Tang Kai Wang Luyi Huang Jie Hu Zhongqi Feng Qingzhu Gao Ailong Huang 

机构地区：[1]Institute for Viral Hepatitis,Key Laboratory of Molecular Biology for Infectious Diseases(Ministry of Education),Department of Infectious Diseases,The Second Affiliated Hospital,Chongqing Medical University,Chongqing,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第3期1208-1223,共16页信号转导与靶向治疗（英文）

基　　金：This work was supported by the China National Natural Science Foundation(grant no.82272975,U20A20392,82072286,82073251);the 111 Project(No.D20028);the Innovative and Entrepreneurial Team of Chongqing Talents Plan,the Natural Science Foundation Project of Chongqing(cstc2019jscx-dxwtBX0019,cstc2021jcyj-bsh0017);Chongqing Medical Scientific Research Project(Joint project of Chongqing Health Commission and Science and Technology Bureau,2023DBXM007);the Kuanren talents program of the second affiliated hospital of Chongqing Medical University,the Program for Youth Innovation in Future Medicine of Chongqing Medical University(W0036,W0101);the Science and Technology Research Program of Chongqing Municipal Education Commission(HZ2021006,KJZD-M202000401);the Postgraduate research and innovation projects of Chongqing Municipal Education Commission(CYB21174).

摘　　要：Hepatitis B virus(HBV)infection is a major risk factor for hepatocellular carcinoma(HCC),but its pathogenic mechanism remains to be explored.The RNA N^(6)-methyladenosine(m^(6)A)reader,YTH(YT521-B homology)domain 2(YTHDF2),plays a critical role in the HCC progression.However,the function and regulatory mechanisms of YTHDF2 in HBV-related HCC remain largely elusive.Here,we discovered that YTHDF2 O-GlcNAcylation was markedly increased upon HBV infection.O-GlcNAc transferase(OGT)-mediated O-GlcNAcylation of YTHDF2 on serine 263 enhanced its protein stability and oncogenic activity by inhibiting its ubiquitination.Mechanistically,YTHDF2 stabilized minichromosome maintenance protein 2(MCM2)and MCM5 transcripts in an m^(6)A-dependent manner,thus promoting cell cycle progression and HBV-related HCC tumorigenesis.Moreover,targeting YTHDF2 O-GlcNAcylation by the OGT inhibitor OSMI-1 significantly suppressed HCC progression.Taken together,our findings reveal a new regulatory mechanism for YTHDF2 and highlight an essential role of YTHDF2 O-GlcNAcylation in RNA m^(6)A methylation and HCC progression.Further description of the molecular pathway has the potential to yield therapeutic targets for suppression of HCC progression due to HBV infection.

关 键 词：HEPATOCELLULAR markedly DF2 

分 类 号：R735.7[医药卫生—肿瘤]