Elevated O-GlcNAcylation promotes gastric cancer cells proliferation by modulating cell cycle related proteins and ERK 1/2 signaling

// Mingzuo Jiang 1, * , Zhaoyan Qiu 3, * , Song Zhang 1, * , Xing Fan 2, * , Xiqiang Cai 1 , Bing Xu 1 , Xiaowei Li 1 , Jinfeng Zhou 1 , Xiangyuan Zhang 1 , Yi Chu 1 , Weijie Wang 1 , Jie Liang 1 , Tamas Horvath 4 , Xiaoyong Yang 4 , Kaichun Wu 1 , Yongzhan Nie 1 , Daiming Fan 1 1 State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi’an, China 2 Institute of Plastic Surgery of The Chinese PLA, The Fourth Military Medical University, Xi’an, China 3 Department of General Surgery, The General Hospital of People’s Liberation Army, 301 Hospital, Beijing, China 4 Department of Molecular Cellular and Developmental Biology, Yale University, New Haven, USA * These authors contributed equally to this work Correspondence to: Yongzhan Nie, email: yongznie@fmmu.edu.cn Daiming Fan, email: fandaim@fmmu.edu.cn Keywords: O-GlcNAc, gastric cancer, cell cycle, ERK 1/2, clinicopathological parameters Received: April 12, 2016 Accepted: August 10, 2016 Published: August 17, 2016 ABSTRACT O-GlcNAc transferase (OGT) is the only enzyme in mammals that catalyzes the attachment of β-D-N-acetylglucosamine (GlcNAc) to serine or threonine residues of target proteins. Hyper-O-GlcNAcylation is becoming increasingly realized as a general feature of cancer and contributes to rapid proliferation of cancer cells. In this study, we demonstrated that O-GlcNAc and OGT levels were increased in all six gastric cancer (GC) cell lines as compared with immortal gastric epithelial cells. Downregulation of the O-GlcNAcylation level by silencing OGT inhibited cell viability and growth rate via the cdk-2, cyclin D1 and ERK 1/2 pathways. In vivo xenograft assays also demonstrated that the hyper-O-GlcNAc level markedly promoted the proliferation of tumors. Moreover, compared with noncancerous tissues, the O-GlcNAcylation level was increased in cancerous tissues. GC patients with higher levels of O-GlcNAcylation exhibited large tumor sizes (≥5 cm), deep tumor invasion (T3 and T4), high AJCC stages (stage III and IV), more lymph node metastases and lower overall survival. Notably, the phosphorylation level of ERK 1/2 was increased progressively with the increase of O-GlcNAcylation in both SGC 7901 and AGS cells. Consistently, human GC tissue arrays also revealed that ERK 1/2 signaling was positively correlated to O-GlcNAcylation ( r = 0.348; P = 0.015). Taken together, here we reported that hyper-O-GlcNAcylation significantly promotes GC cells proliferation by modulating cell cycle related proteins and ERK 1/2 signaling, suggesting that inhibition of OGT may be a potential novel therapeutic target of GC.