Back to Search
Start Over
The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis.
- Source :
-
Nature communications [Nat Commun] 2017 May 05; Vol. 8, pp. 15280. Date of Electronic Publication: 2017 May 05. - Publication Year :
- 2017
-
Abstract
- O-GlcNAcylation has been implicated in the tumorigenesis of various tissue origins, but its function in liver tumorigenesis is not clear. Here, we demonstrate that O-GlcNAcylation can enhance the expression, stability and function of Yes-associated protein (YAP), the downstream transcriptional regulator of the Hippo pathway and a potent oncogenic factor in liver cancer. O-GlcNAcylation induces transformative phenotypes of liver cancer cells in a YAP-dependent manner. An O-GlcNAc site of YAP was identified at Thr241, and mutating this site decreased the O-GlcNAcylation, stability, and pro-tumorigenic capacities of YAP, while increasing YAP phosphorylation. Importantly, we found via in vitro cell-based and in vivo mouse model experiments that O-GlcNAcylation of YAP was required for high-glucose-induced liver tumorigenesis. Interestingly, a positive feedback between YAP and global cellular O-GlcNAcylation is also uncovered. We conclude that YAP O-GlcNAcylation is a potential therapeutic intervention point for treating liver cancer associated with high blood glucose levels and possibly diabetes.
- Subjects :
- Adaptor Proteins, Signal Transducing metabolism
Animals
Carcinogenesis drug effects
Carcinogenesis pathology
Cell Line, Tumor
Gene Expression Regulation, Neoplastic drug effects
Glycosylation drug effects
Humans
Liver Neoplasms genetics
Liver Neoplasms pathology
Male
Mice, Inbred BALB C
N-Acetylglucosaminyltransferases metabolism
Phosphoproteins metabolism
Protein Stability drug effects
Threonine metabolism
Transcription Factors
Transcription, Genetic drug effects
YAP-Signaling Proteins
beta-Transducin Repeat-Containing Proteins metabolism
Acetylglucosamine metabolism
Carcinogenesis metabolism
Glucose toxicity
Liver Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 8
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 28474680
- Full Text :
- https://doi.org/10.1038/ncomms15280