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Oncotarget. 2016 Sep 20;7(38):61390-61402. doi: 10.18632/oncotarget.11359.

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

Author information

1
State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
2
Department of General Surgery, The General Hospital of People's Liberation Army, 301 Hospital, Beijing, China.
3
Institute of Plastic Surgery of The Chinese PLA, The Fourth Military Medical University, Xi'an, China.
4
Department of Molecular Cellular and Developmental Biology, Yale University, New Haven, USA.

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.

KEYWORDS:

ERK 1/2; O-GlcNAc; cell cycle; clinicopathological parameters; gastric cancer

PMID:
27542217
PMCID:
PMC5308659
DOI:
10.18632/oncotarget.11359
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare that they have no conflicts of interest.

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