J Biol Chem 2012 Apr 27;287(16):12904-12. Epub 2012 Feb 27.
Department of Cellular and Molecular Physiology, Section of Comparative Medicine and Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
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.
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