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

Autor:	Ferrer CM; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA., Lynch TP; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA., Sodi VL; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA., Falcone JN; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA., Schwab LP; Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA., Peacock DL; Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA., Vocadlo DJ; Departments of Chemistry and Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada., Seagroves TN; Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA., Reginato MJ; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. Electronic address: mauricio.reginato@drexelmed.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2014 Jun 05; Vol. 54 (5), pp. 820-31. Date of Electronic Publication: 2014 May 22.
DOI:	10.1016/j.molcel.2014.04.026
Abstrakt:	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. (Copyright © 2014 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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