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High Glucose Stimulates Tumorigenesis in Hepatocellular Carcinoma Cells Through AGER-Dependent O-GlcNAcylation of c-Jun.
- Source :
- Diabetes; Mar2016, Vol. 65 Issue 3, p619-632, 14p, 1 Diagram, 7 Graphs
- Publication Year :
- 2016
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- LIVER cancer
DIABETES
GLUCOSE
GLYCOSYLATION
PROTEINS
PROTEIN metabolism
CARCINOGENESIS
ANIMAL experimentation
BLOOD sugar
CELL lines
CELL physiology
CELLULAR signal transduction
EPITHELIAL cells
FLUORESCENT antibody technique
GAS chromatography
HEPATOCELLULAR carcinoma
IMMUNOBLOTTING
IMMUNOHISTOCHEMISTRY
LIVER tumors
MASS spectrometry
MICE
POLYMERASE chain reaction
TRANSFERASES
WESTERN immunoblotting
REVERSE transcriptase polymerase chain reaction
PRECIPITIN tests
METABOLISM
Subjects
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 65
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 113276614
- Full Text :
- https://doi.org/10.2337/db15-1057