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 Seagroves, Mauricio J. Reginato

Research output: Contribution to journalArticle

121 Citations (Scopus)

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 byincreasing O-GlcNAc transferase (OGT) and/or decreasing O-GlcNAcase (OGA) levels. Reducing O-GlcNAcylation inhibits oncogenesis. Here, we demonstrate thatO-GlcNAcylation regulates glycolysis in cancer cellsvia hypoxia-inducible factor 1 (HIF-1α) and its transcriptional target GLUT1. Reducing O-GlcNAcylation increases α-ketoglutarate, HIF-1 hydroxylation, andinteraction 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.

Original languageEnglish (US)
Pages (from-to)820-831
Number of pages12
JournalMolecular Cell
Volume54
Issue number5
DOIs
StatePublished - Jun 5 2014

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Hypoxia-Inducible Factor 1
Survival
Neoplasms
Transcription Factor CHOP
Hexosamines
Physiological Stress
Endoplasmic Reticulum Stress
Acetylglucosamine
Biosynthetic Pathways
Glycolysis
Hydroxylation
Cell Survival
Carcinogenesis
Proteins
Apoptosis
Breast Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Ferrer, C. M., Lynch, T. P., Sodi, V. L., Falcone, J. N., Schwab, L. P., Peacock, D. L., ... Reginato, M. J. (2014). O-GlcNAcylation Regulates Cancer Metabolism and Survival Stress Signaling via Regulation of the HIF-1 Pathway. Molecular Cell, 54(5), 820-831. https://doi.org/10.1016/j.molcel.2014.04.026

O-GlcNAcylation Regulates Cancer Metabolism and Survival Stress Signaling via Regulation of the HIF-1 Pathway. / Ferrer, Christina M.; Lynch, Thomas P.; Sodi, Valerie L.; Falcone, John N.; Schwab, Luciana P.; Peacock, Danielle L.; Vocadlo, David J.; Seagroves, Tiffany; Reginato, Mauricio J.

In: Molecular Cell, Vol. 54, No. 5, 05.06.2014, p. 820-831.

Research output: Contribution to journalArticle

Ferrer, CM, Lynch, TP, Sodi, VL, Falcone, JN, Schwab, LP, Peacock, DL, Vocadlo, DJ, Seagroves, T & Reginato, MJ 2014, 'O-GlcNAcylation Regulates Cancer Metabolism and Survival Stress Signaling via Regulation of the HIF-1 Pathway', Molecular Cell, vol. 54, no. 5, pp. 820-831. https://doi.org/10.1016/j.molcel.2014.04.026
Ferrer, Christina M. ; Lynch, Thomas P. ; Sodi, Valerie L. ; Falcone, John N. ; Schwab, Luciana P. ; Peacock, Danielle L. ; Vocadlo, David J. ; Seagroves, Tiffany ; Reginato, Mauricio J. / O-GlcNAcylation Regulates Cancer Metabolism and Survival Stress Signaling via Regulation of the HIF-1 Pathway. In: Molecular Cell. 2014 ; Vol. 54, No. 5. pp. 820-831.
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