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

Christina M Ferrer; Thomas P Lynch; Valerie L Sodi; John N Falcone; Luciana P Schwab; Danielle L Peacock; David J Vocadlo; Tiffany N Seagroves; Mauricio J Reginato

doi:10.1016/j.molcel.2014.04.026

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

Journal article

Open access

Peer reviewed

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

Christina M Ferrer, Thomas P Lynch, Valerie L Sodi, John N Falcone, Luciana P Schwab, Danielle L Peacock, David J Vocadlo, Tiffany N Seagroves and Mauricio J Reginato

Molecular cell, v 54(5), pp 820-831

05 Jun 2014

DOI: https://doi.org/10.1016/j.molcel.2014.04.026

PMID: 24857547

Featured in Collection : UN Sustainable Development Goals @ Drexel

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Abstract

Neoplasm Transplantation

Humans

Acetylglucosamine - metabolism

Breast Neoplasms - metabolism

Hypoxia-Inducible Factor 1, alpha Subunit - metabolism

Proteolysis

Female

Hydroxylation

Signal Transduction

Cell Survival

Kaplan-Meier Estimate

Glycosylation

N-Acetylglucosaminyltransferases - metabolism

Citric Acid Cycle

Animals

Breast Neoplasms - pathology

Mice, Nude

Endoplasmic Reticulum Stress

Cell Line, Tumor

Glycolysis

Breast Neoplasms - mortality

Mice

Protein Processing, Post-Translational

Proteasome Endopeptidase Complex - metabolism

Transcription Factor CHOP - metabolism

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.

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368 citations in Scopus

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Title: O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway
Creators: Christina M Ferrer - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
Thomas P Lynch - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
Valerie L Sodi - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
John N Falcone - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
Luciana P Schwab - Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
Danielle L Peacock - Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
David J Vocadlo - Departments of Chemistry and Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
Tiffany N Seagroves - Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
Mauricio J Reginato - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. Electronic address: mauricio.reginato@drexelmed.edu
Publication Details: Molecular cell, v 54(5), pp 820-831
Publisher: Elsevier; United States
Grant note: F31 CA183574 / NCI NIH HHS CA138488 / NCI NIH HHS R01 CA155413 / NCI NIH HHS CA155413 / NCI NIH HHS CA183574 / NCI NIH HHS R01 CA138488 / NCI NIH HHS
Resource Type: Journal article
Language: English
Academic Unit: Biochemistry and Molecular Biology
Web of Science ID: WOS:000340626100011
Scopus ID: 2-s2.0-84901946068
Other Identifier: 991014878066704721

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Collaboration types: Domestic collaboration; International collaboration
Web of Science research areas: Biochemistry & Molecular Biology; Cell Biology

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

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UN Sustainable Development Goals (SDGs)

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