O-GlcNAc transferase is involved in glucocorticoid receptor-mediated transrepression

J Biol Chem. 2012 Apr 13;287(16):12904-12. doi: 10.1074/jbc.M111.303792. Epub 2012 Feb 27.


Recruitment of O-GlcNAc transferase (OGT) to promoters plays an important role in gene repression. Glucocorticoid signaling represses the transcriptional activities of NF-κB and AP-1 through direct binding, yet the molecular mechanisms remain to be elucidated. Here we report that OGT is an important component of GR-mediated transrepression. OGT associates with ligand-bound GR in a multi-protein repression complex. Overexpression of OGT potentiates the GR transrepression pathway, whereas depletion of endogenous OGT by RNA interference abolishes the repression. The recruitment of OGT by GR leads to increased O-GlcNAcylation and decreased phosphorylation of RNA polymerase II on target genes. Functionally, overexpression of OGT enhances glucocorticoid-induced apoptosis in resistant cell lines while knockdown of OGT prevents sensitive cell lines from apoptosis. These studies identify a molecular mechanism of GR transrepression, and highlight the function of O-GlcNAc in hormone signaling.

Publication types

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

MeSH terms

  • Acetylglucosamine / metabolism
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / pharmacology
  • Apoptosis / physiology
  • Cell Line, Tumor
  • Drug Design
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology*
  • HEK293 Cells
  • Humans
  • Hydrocortisone / metabolism
  • Hydrocortisone / pharmacology
  • Lung Neoplasms
  • N-Acetylglucosaminyltransferases / genetics*
  • N-Acetylglucosaminyltransferases / metabolism*
  • NF-kappa B / metabolism
  • Nuclear Receptor Coactivator 2 / metabolism
  • RNA Polymerase II / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Glucocorticoid / genetics*
  • Receptors, Glucocorticoid / metabolism*
  • Signal Transduction / physiology


  • Anti-Inflammatory Agents
  • NCOA2 protein, human
  • NF-kappa B
  • Nuclear Receptor Coactivator 2
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Glucocorticoid
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • RNA Polymerase II
  • Acetylglucosamine
  • Hydrocortisone