O-GlcNAc in cancer: An Oncometabolism-fueled vicious cycle

  • John A. Hanover
  • Weiping Chen
  • Michelle R. Bond


Cancer cells exhibit unregulated growth, altered metabolism, enhanced metastatic potential and altered cell surface glycans. Fueled by oncometabolism and elevated uptake of glucose and glutamine, the hexosamine biosynthetic pathway (HBP) sustains glycosylation in the endomembrane system. In addition, the elevated pools of UDP-GlcNAc drives the O-GlcNAc modification of key targets in the cytoplasm, nucleus and mitochondrion. These targets include transcription factors, kinases, key cytoplasmic enzymes of intermediary metabolism, and electron transport chain complexes. O-GlcNAcylation can thereby alter epigenetics, transcription, signaling, proteostasis, and bioenergetics, key ‘hallmarks of cancer’. In this review, we summarize accumulating evidence that many cancer hallmarks are linked to dysregulation of O-GlcNAc cycling on cancer-relevant targets. We argue that onconutrient and oncometabolite-fueled elevation increases HBP flux and triggers O-GlcNAcylation of key regulatory enzymes in glycolysis, Kreb’s cycle, pentose-phosphate pathway, and the HBP itself. The resulting rerouting of glucose metabolites leads to elevated O-GlcNAcylation of oncogenes and tumor suppressors further escalating elevation in HBP flux creating a ‘vicious cycle’. Downstream, elevated O-GlcNAcylation alters DNA repair and cellular stress pathways which influence oncogenesis. The elevated steady-state levels of O-GlcNAcylated targets found in many cancers may also provide these cells with a selective advantage for sustained growth, enhanced metastatic potential, and immune evasion in the tumor microenvironment.


O-GlcNAc Epigenetics Cancer Oncometabolism Oxidative phosphorylation Glycolysis DNA damage Tumor suppressors Oncogenes Hexosamine biosythetic pathway 

Supplementary material

10863_2018_9751_MOESM1_ESM.xlsx (16 kb)
Supplemental Table I. Listing of the top 50 human genes mutated in diverse tumor types derived from the Cancer Genome atlas. Details of the ranking analysis are available elsewhere (Lawrence et al. 2014). (XLSX 15 kb)


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© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018

Authors and Affiliations

  1. 1.Laboratory of Cell Biochemistry and Molecular BiologyNIDDK, NIHBethesdaUSA
  2. 2.NIDDK Genomics CoreBethesdaUSA

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