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.
Highlights
Gastric cancer (GC) is the third most common cancer in China [1]
We demonstrated that O-GlcNAc and O-GlcNAc transferase (OGT) levels were increased in all six gastric cancer (GC) cell lines as compared with immortal gastric epithelial cells
To evaluate the relationship between O-GlcNAcylation and gastric cancer, the OGT and O-GlcNAcylation levels were analyzed in various gastric cancer cell lines and immortal gastric epithelial cells (GES)
Summary
Gastric cancer (GC) is the third most common cancer in China [1]. Established cell lines and animal models have been vividly intimated the important aspects of GC and provided significant clues to the critical molecular events during the process of the GC development. One of the remarkable features of cancer cells is the increased in aerobic glycolysis and increased in the rate of glucose uptake and utilization, which is termed the Warburg effect [7]. A high rate of aerobic www.impactjournals.com/oncotarget glycolysis and glucose uptake would increase the HBP flux, leading to the elevation of O-GlcNAcylation in cancerous tissues [6,7,8]. O-GlcNAcylation regulates the activities of a wide panel of proteins involved in almost all aspects of cell biology, such as cell proliferation, survival, energy metabolism, migration and invasion [5, 6, 16, 17]
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