title: O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Ferrer
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Lynch
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Sodi
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Falcone
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Luciana P
authors.initials: LP
authors.lastname: Schwab
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Peacock
authors.affiliation: Departments of Chemistry and Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
authors.forename: David J
authors.initials: DJ
authors.lastname: Vocadlo
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Tiffany N
authors.initials: TN
authors.lastname: Seagroves
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. Electronic address: mauricio.reginato@drexelmed.edu.
authors.forename: Mauricio J
authors.initials: MJ
authors.lastname: Reginato
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D002952:Citric Acid Cycle; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006019:Glycolysis; D006031:Glycosylation; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D009368:Neoplasm Transplantation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C497249:DDIT3 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051742:Transcription Factor CHOP; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D046988:Proteasome Endopeptidase Complex; D000117:Acetylglucosamine