High Glucose Stimulates Tumorigenesis in Hepatocellular Carcinoma Cells Through AGER-Dependent O-GlcNAcylation of c-Jun

• Published in: Diabetes (New York, N.Y.) Vol. 65; no. 3; pp. 619 - 632
• Main Authors: Qiao, Yongxia, Zhang, Xiao, Zhang, Yue, Wang, Yulan, Xu, Yanfeng, Liu, Xiangfan, Sun, Fenyong, Wang, Jiayi
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-03-2016
• Subjects: Acylation; Animals; Blood Glucose - metabolism; Blotting, Western; Carcinogenesis - metabolism; Carcinoma, Hepatocellular - metabolism; Cell Line, Tumor; Cell Proliferation; Cells; Diabetes; Diabetes Mellitus, Experimental - metabolism; Epidemiology; Fluorescent Antibody Technique; Gas Chromatography-Mass Spectrometry; Glycosylation; Hep G2 Cells; Humans; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Liver Neoplasms - metabolism; Mice; Mice, Inbred BALB C; N-Acetylglucosaminyltransferases - metabolism; Proto-Oncogene Proteins c-jun - metabolism; Receptor for Advanced Glycation End Products - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Tumors
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db15-1057

Epidemiologic studies suggest that hepatocellular carcinoma (HCC) has a strong relationship with diabetes. However, the underlying molecular mechanisms still remain unclear. Here, we demonstrated that high glucose (HG), one of the main characteristics of diabetes, was capable of accelerating tumorigenesis in HCC cells. Advanced glycosylation end product-specific receptor (AGER) was identified as a stimulator during this process. Mechanistically, AGER activated a hexosamine biosynthetic pathway, leading to enhanced O-GlcNAcylation of target proteins. Notably, AGER was capable of increasing activity and stability of proto-oncoprotein c-Jun via O-GlcNAcylation of this protein at Ser73. Interestingly, c-Jun can conversely enhance AGER transcription. Thereby, a positive autoregulatory feedback loop that stimulates diabetic HCC was established. Finally, we found that AG490, an inhibitor of Janus kinase, has the ability to impair AGER expression and its functions in HCC cells. In conclusion, AGER and its functions to stimulate O-GlcNAcylation are important during liver tumorigenesis, when high blood glucose levels are inadequately controlled.