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

Nat Commun. 2017 May 5:8:15280. doi: 10.1038/ncomms15280.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Carcinogenesis / drug effects
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glucose / toxicity*
  • Glycosylation / drug effects
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • 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


  • Adaptor Proteins, Signal Transducing
  • Phosphoproteins
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • beta-Transducin Repeat-Containing Proteins
  • Threonine
  • N-Acetylglucosaminyltransferases
  • UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase
  • Glucose
  • Acetylglucosamine