O-GlcNAcylation of SPOP promotes carcinogenesis in hepatocellular carcinoma

作者全名:"Zhou, Peng; Chang, Wen-yi; Gong, De-ao; Huang, Lu-yi; Liu, Rui; Liu, Yi; Xia, Jie; Wang, Kai; Tang, Ni; Huang, Ai-long"

作者地址:"[Zhou, Peng; Chang, Wen-yi; Gong, De-ao; Huang, Lu-yi; Liu, Rui; Liu, Yi; Xia, Jie; Wang, Kai; Tang, Ni; Huang, Ai-long] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Dis,Minist Educ, Chongqing, Peoples R China"

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

来源:ONCOGENE

ESI学科分类:MOLECULAR BIOLOGY & GENETICS

WOS号:WOS:000909162100002

JCR分区:Q1

影响因子:8

年份:2023

卷号:42

期号:10

开始页:725

结束页:736

文献类型:Article

关键词: 

摘要:"Aberrantly elevated O-GlcNAcylation level is commonly observed in human cancer patients, and has been proposed as a potential therapeutic target. Speckle-type POZ protein (SPOP), an important substrate adaptor of cullin3-RING ubiquitin ligase, plays a key role in the initiation and development of various cancers. However, the regulatory mechanisms governing SPOP and its function during hepatocellular carcinoma (HCC) progression remain unclear. Here, we show that, in HCC, SPOP is highly O-GlcNAcylated by O-GlcNAc transferase (OGT) at Ser96. In normal liver cells, the SPOP protein mainly localizes in the cytoplasm and mediates the ubiquitination of the oncoprotein neurite outgrowth inhibitor-B (Nogo-B) (also known as reticulon 4 B) by recognizing its N-terminal SPOP-binding consensus (SBC) motifs. However, O-GlcNAcylation of SPOP at Ser96 increases the nuclear positioning of SPOP in hepatoma cells, alleviating the ubiquitination of the Nogo-B protein, thereby promoting HCC progression in vitro and in vivo. In addition, ablation of O-GlcNAcylation by an S96A mutation increased the cytoplasmic localization of SPOP, thereby inhibiting the Nogo-B/c-FLIP cascade and HCC progression. Our findings reveal a novel post-translational modification of SPOP and identify a novel SPOP substrate, Nogo-B, in HCC. Intervention with the hyper O-GlcNAcylation of SPOP may provide a novel strategy for HCC treatment."

基金机构:"National Natural Science Foundation of China [U20A20392, 82072286, 82073251]; 111 Project [D20028]; Innovative and Entrepreneurial Team of Chongqing Talents Plan; Natural Science Foundation Project of Chongqing [cstc2019jscx-dxwtBX0019]; Chongqing Medical Scientific Research Project [2023DBXM007]; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University; Program for Youth Innovation in Future Medicine, Chongqing Medical University [W0036, W0101]; Science and Technology Research Program of Chongqing Municipal Education Commission [HZ2021006, JZD-M202000401]"

基金资助正文:"This work was supported by the National Natural Science Foundation of China (Grant No. U20A20392, AH; 82072286, NT; 82073251, KW), the 111 Project (No. D20028, AH), the Innovative and Entrepreneurial Team of Chongqing Talents Plan, Natural Science Foundation Project of Chongqing (cstc2019jscx-dxwtBX0019, NT), Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2023DBXM007, NT), Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University, Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0036, NT; W0101, KW), and Science and Technology Research Program of Chongqing Municipal Education Commission grants HZ2021006 (NT) and JZD-M202000401 (NT)."