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

Abstract

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.

Identification of biomarkers, pathways and potential therapeutic agents for white adipocyte insulin resistance using bioinformatics analysis

“…The MF analysis of GO suggested that the DEGs were the most significant enriched in protein binding, suggesting that the interaction of two or more proteins played an important role in the adipocyte insulin resistance. Additionally, KEGG enrichment analysis of DEGs showed that these DEGs were mapped in cytokinecytokine receptor interaction, TNF signalling pathway, toll-like receptor signalling pathway, pathways in cancer, all which were consistent with the previous demonstration that white adipocyte insulin resistance had cross-talking with inflammation and tumorigenesis [38,39].…”

The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis

“…O-GlcNAcylation is an important posttranslational modification of proteins and plays pro-oncogenic roles in several types of cancer, including liver cancer4041424344. O-GlcNAcylation of the Jun proto-oncogene (c-Jun) and Tribbles pseudokinase 2 (TRIB2) has been recently reported to stimulate liver tumorigenesis4546. Interestingly, both c-Jun and TRIB2 are nuclear proteins.…”

circRNA_104075 stimulates YAP-dependent tumorigenesis through the regulation of HNF4a and may serve as a diagnostic marker in hepatocellular carcinoma

“…The liver cancer cell lines Bel-7402 (Cell bank of Chinese Academy of Sciences, Shanghai, China), SMMC-7721 (Cell bank of Chinese Academy of Sciences, Shanghai, China), Huh7 (Cobioer, Nanjing, China), HepG2 (Cobioer, Nanjing, China), Hep1 (Cell bank of Chinese Academy of Sciences, Shanghai, China), and Bel-7404 (Cell bank of Chinese Academy of Sciences, Shanghai, China) and the hepatocyte lines THLE-3 (Biovector, NTCC, Beijing, China) and HL-7702 (Cell bank of Chinese Academy of Sciences, Shanghai, China) were cultured in DMEM. TEAD, CREB, TFCP2, STAT3, c-Myc, FOXO1, TEAD-sh1, CREB-sh1, TFCP2-sh1, STAT3-sh1, c-Myc-sh1, and FOXO1-sh1 plasmids were acquired from previous studies 40 , 42 , 61 – 66 . HNF4a plasmids were purchased from Origene (Beijing, China).…”