O-GlcNAcylation promotes colorectal cancer metastasis via the miR-101-O-GlcNAc/EZH2 regulatory feedback circuit

被引:104
作者
Jiang, Mingzuo [1 ,2 ]
Xu, Bing [1 ,2 ,3 ]
Li, Xiaowei [1 ,2 ]
Shang, Yulong [1 ,2 ]
Chu, Yi [1 ,2 ]
Wang, Weijie [1 ,2 ]
Chen, Di [1 ,2 ]
Wu, Nan [1 ,2 ,4 ]
Hu, Sijun [1 ,2 ]
Zhang, Song [1 ,2 ]
Li, Mengbin [1 ,2 ]
Wu, Kaichun [1 ,2 ]
Yang, Xiaoyong [5 ]
Liang, Jie [1 ,2 ]
Nie, Yongzhan [1 ,2 ]
Fan, Daiming [1 ,2 ]
机构
[1] Fourth Mil Med Univ, Natl Clin Res Ctr Digest Dis, State Key Lab Canc Biol, Xian, Shaanxi, Peoples R China
[2] Fourth Mil Med Univ, Xijing Hosp Digest Dis, Xian, Shaanxi, Peoples R China
[3] Xi An Jiao Tong Univ, Affiliated Hosp 2, Dept Gastroenterol, Xian 710004, Shaanxi, Peoples R China
[4] Northwest Univ, Fac Life Sci, Lab Tissue Engn, Xian, Shaanxi, Peoples R China
[5] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA
基金
中国国家自然科学基金;
关键词
EPITHELIAL-MESENCHYMAL TRANSITION; BETA-N-ACETYLGLUCOSAMINE; GLCNAC TRANSFERASE; E-CADHERIN; C-MYC; EZH2; COLON; PROTEIN; EXPRESSION; MIGRATION;
D O I
10.1038/s41388-018-0435-5
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Advanced colorectal cancer (CRC) is one of the deadliest cancers, and the 5-year survival rate of patients with metastasis is extremely low. The epithelial-mesenchymal transition (EMT) is considered essential for metastatic CRC, but the fundamental molecular basis underlying this effect remains unknown. Here, we identified that O-GlcNAcylation, a unique posttranslational modification (PTM) involved in cancer metabolic reprogramming, increased the metastatic capability of CRC. The levels of O-GlcNAcylation were increased in the metastatic CRC tissues and cell lines, which likely promoted the EMT by enhancing EZH2 protein stability and function. The CRC patients with higher levels of O-GlcNAcylation exhibited greater lymph node metastasis potential and lower overall survival. Bioinformatic analysis and luciferase reporter assays revealed that both O-GlcNAcylation transferase (OGT) and EZH2 are posttranscriptionally inhibited by microRNA-101. In addition, O-GlcNAcylation and H3K27me3 modification in the miR-101 promoter region further inhibited the transcription of miR-101, resulting in the upregulation of OGT and EZH2 in metastatic CRC, thus forming a vicious cycle. In this study, we demonstrated that O-GlcNAcylation, which is negatively regulated by microRNA-101, likely promotes CRC metastasis by enhancing EZH2 protein stability and function. Reducing O-GlcNAcylation may be a potential therapeutic strategy for metastatic CRC.
引用
收藏
页码:301 / 316
页数:16
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