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.

O‐GlcNAcylation promotes colorectal cancer progression by regulating protein stability and potential catcinogenic function of DDX5

“…Clinical studies have also found that higher levels of O‐GlcNAcylation are involved in the malignant clinicopathological features of various cancer patients . In gastric carcinoma, poorly differentiated tumours (grades II and III) showed significantly higher expression of O‐GlcNAcylation than grade I tumours . At the same time, we detected the expression of O‐GlcNAcylation and DDX5 in colorectal cancer tissues and matched normal controls.…”

“…Therefore, we speculate that OGT regulation of DDX5 may be post‐transcriptional regulation. We used YinOYang 1.2 Server (www.cbs.dtu.dk/services/YinOYang) to predict the presence of O‐GlcNAcylation sites in DDX5, suggesting that DDX5 can be directly modified by O‐GlcNAcylation (Figure D). Therefore, we detected the stable binding products of OGT and DDX5 by co‐IP.…”

miR-483 is down-regulated in gastric cancer and suppresses cell proliferation, invasion and protein O-GlcNAcylation by targeting OGT

“…Consistent with these previous studies, we indicated that modulating expression of miR-483 could influence total protein O-GlcNAcylation levels in gastric cancer cells. OGT has been reported to consistently increase in a wide variety of human cancers including gastric cancer and is involved in the initiation and development of cancers by enhancing cell proliferation and invasion [29][30][31]. However, the mechanism through which OGT is maintained at a high expression level in cancer cells remains unknown.…”

Regulation and clinical significance of O-GlcNAc transferase in cancer

“…Moreover, the migrating and invasive capability of HepG2 is heightened by elevated O-GlcNAcylation, because this modification decreases E-cadherin expression and increases MMP-1, MMP-2 and MMP-3 expression [36]. OGT mRNA level and protein O-GlcNAc modification are progressively increased during the carcinogenesis of gastric cancer, and patients with hyper-O-GlcNAcylation have poor prognosis [37,38,99]. Reduction of O-GlcNAcylation by OGT siRNA inhbits and increment of this modification by OGA inhibitors enhances cell proliferation and tumor growth of gastric cancer through regulating the activation of ERK signaling pathway and the expression of CDK-2 and cyclin D1 [37].…”

“…Given the myriad functions concerned with O-GlcNAcylation, it is exceedingly reasonable that this posttranslational modification plays a fundamental role in the etiology of tumors [6,14,[26][27][28]. Indeed, O-GlcNAcylation is deregulated in many cancer types, including breast [29,30], pancreatic [31], prostate [32,33], colorectal [34,35], lung [34], liver [36], gastric [37,38], laryngeal [39], bladder [40], endometrial [41], esophageal squamous cell carcinoma [42], and nonsolid cancers such as chronic lymphocytic leukemia [43], and contributes to cancer cell metabolic reprogramming, cell proliferation, survival, angiogenesis, invasion, metastasis and cancer cell epigenetics [14,44].…”