Elevated O-GlcNAcylation promotes gastric cancer cells proliferation by modulating cell cycle related proteins and ERK 1/2 signaling
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Mingzuo Jiang1,*, Zhaoyan Qiu3,*, Song Zhang1,*, Xing Fan2,*, Xiqiang Cai1, Bing Xu1, Xiaowei Li1, Jinfeng Zhou1, Xiangyuan Zhang1, Yi Chu1, Weijie Wang1, Jie Liang1, Tamas Horvath4, Xiaoyong Yang4, Kaichun Wu1, Yongzhan Nie1, Daiming Fan1
1State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi’an, China
2Institute of Plastic Surgery of The Chinese PLA, The Fourth Military Medical University, Xi’an, China
3Department of General Surgery, The General Hospital of People’s Liberation Army, 301 Hospital, Beijing, China
4Department of Molecular Cellular and Developmental Biology, Yale University, New Haven, USA
*These authors contributed equally to this work
Yongzhan Nie, email: [email protected]
Daiming Fan, email: [email protected]
Keywords: O-GlcNAc, gastric cancer, cell cycle, ERK 1/2, clinicopathological parameters
Received: April 12, 2016 Accepted: August 10, 2016 Published: August 17, 2016
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.
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