title: Elevated O-GlcNAcylation promotes gastric cancer cells proliferation by modulating cell cycle related proteins and ERK 1/2 signaling.
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.
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Mingzuo
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of General Surgery, The General Hospital of People's Liberation Army, 301 Hospital, Beijing, China.
authors.forename: Zhaoyan
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Institute of Plastic Surgery of The Chinese PLA, The Fourth Military Medical University, Xi'an, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Xiqiang
authors.initials: X
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Xiangyuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chu
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Molecular Cellular and Developmental Biology, Yale University, New Haven, USA.
authors.forename: Tamas
authors.initials: T
authors.lastname: Horvath
authors.affiliation: Department of Molecular Cellular and Developmental Biology, Yale University, New Haven, USA.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.affiliation: State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013274:Stomach Neoplasms / Q000473:pathology*; D013912:Threonine / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: C530104:CCND1 protein, human; D034741:RNA, Small Interfering; D019938:Cyclin D1; D013912:Threonine; D012694:Serine; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000117:Acetylglucosamine
keywords: ERK 1/2; O-GlcNAc; cell cycle; clinicopathological parameters; gastric cancer