O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway.
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.
Mesh Terms:
Acetylglucosamine, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Survival, Citric Acid Cycle, Endoplasmic Reticulum Stress, Female, Glycolysis, Glycosylation, Humans, Hydroxylation, Hypoxia-Inducible Factor 1, alpha Subunit, Kaplan-Meier Estimate, Mice, Mice, Nude, N-Acetylglucosaminyltransferases, Neoplasm Transplantation, Proteasome Endopeptidase Complex, Protein Processing, Post-Translational, Proteolysis, Signal Transduction, Transcription Factor CHOP
Acetylglucosamine, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Survival, Citric Acid Cycle, Endoplasmic Reticulum Stress, Female, Glycolysis, Glycosylation, Humans, Hydroxylation, Hypoxia-Inducible Factor 1, alpha Subunit, Kaplan-Meier Estimate, Mice, Mice, Nude, N-Acetylglucosaminyltransferases, Neoplasm Transplantation, Proteasome Endopeptidase Complex, Protein Processing, Post-Translational, Proteolysis, Signal Transduction, Transcription Factor CHOP
Mol. Cell
Date: Jun. 05, 2014
PubMed ID: 24857547
View in: Pubmed Google Scholar
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