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O-GlcNAc in cancer biology

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Abstract

O-linked β-N-actylglucosamine (O-GlcNAc) is a carbohydrate post-translational modification on hydroxyl groups of serine and/or threonine residues of cytosolic and nuclear proteins. Analogous to phosphorylation, O-GlcNAcylation plays crucial regulatory roles in a variety of cellular processes. O-GlcNAc was termed a nutritional sensor, as global levels of the modification are elevated in response to increased glucose and glutamine flux into the hexosamine biosynthetic pathway. A unique feature of cancer cell energy metabolism is a shift from oxidative phosphorylation to the less efficient glycolytic pathway (Warburg effect), necessitating greatly increased glucose uptake. Additionally, to help meet increased biosynthetic demands, cancer cells also up-regulate glutamine uptake. This led us to hypothesize that the universal feature of increased glucose and glutamine uptake by cancer cells might be linked to increased O-GlcNAc levels. Indeed, recent work in many different cancer types now indicates that hyper-O-GlcNAcylation is a general feature of cancer and contributes to transformed phenotypes. In this review, we describe known/potential links between hyper-O-GlcNAcylation and specific hallmarks of cancer, including cancer cell proliferation, survival, cell stresses, invasion and metastasis, aneuploidy, and energy metabolism. We also discuss inhibition of hyper-O-GlcNAcylation as a potential novel therapeutic target for cancer treatment.

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Abbreviations

HBP:

Hexosamine biosynthetic pathway

GlcNAc:

N-acetylglucosamine

PDAC:

Pancreatic ductal adenocarcinoma

OGA:

O-GlcNAcase

HPDE:

Human pancreatic duct epithelial cell

PPP:

Pentose phosphate pathway

HSR:

Heat shock response

EMT:

Epithelial to mesenchymal transition

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  1. Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245 N 15th St. New College Building Room 10112, Philadelphia, PA, 19102, USA

    Zhiyuan Ma & Keith Vosseller

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  1. Zhiyuan Ma
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Ma, Z., Vosseller, K. O-GlcNAc in cancer biology. Amino Acids 45, 719–733 (2013). https://doi.org/10.1007/s00726-013-1543-8

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