O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway

Mol Cell. 2014 Jun 5;54(5):820-31. doi: 10.1016/j.molcel.2014.04.026. Epub 2014 May 22.


The hexosamine biosynthetic pathway elevates posttranslational addition of O-linked β-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. Cancer cells elevate total O-GlcNAcylation by increasing O-GlcNAc transferase (OGT) and/or decreasing O-GlcNAcase (OGA) levels. Reducing O-GlcNAcylation inhibits oncogenesis. Here, we demonstrate that O-GlcNAcylation regulates glycolysis in cancer cells via hypoxia-inducible factor 1 (HIF-1α) and its transcriptional target GLUT1. Reducing O-GlcNAcylation increases α-ketoglutarate, HIF-1 hydroxylation, and interaction with von Hippel-Lindau protein (pVHL), resulting in HIF-1α degradation. Reducing O-GlcNAcylation in cancer cells results in activation of endoplasmic reticulum (ER) stress and cancer cell apoptosis mediated through C/EBP homologous protein (CHOP). HIF-1α and GLUT1 are critical for OGT-mediated regulation of metabolic stress, as overexpression of stable HIF-1 or GLUT1 rescues metabolic defects. Human breast cancers with high levels of HIF-1α contain elevated OGT, and lower OGA levels correlate independently with poor patient outcome. Thus, O-GlcNAcylation regulates cancer cell metabolic reprograming and survival stress signaling via regulation of HIF-1α.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism
  • Animals
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Survival
  • Citric Acid Cycle
  • Endoplasmic Reticulum Stress
  • Female
  • Glycolysis
  • Glycosylation
  • Humans
  • Hydroxylation
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Nude
  • N-Acetylglucosaminyltransferases / metabolism
  • Neoplasm Transplantation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Processing, Post-Translational*
  • Proteolysis
  • Signal Transduction
  • Transcription Factor CHOP / metabolism


  • DDIT3 protein, human
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Transcription Factor CHOP
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • Proteasome Endopeptidase Complex
  • Acetylglucosamine