O-GlcNAc signaling: a metabolic link between diabetes and cancer?

doi:10.1016/j.tibs.2010.04.005

Trends in Biochemical Sciences

Volume 35, Issue 10, October 2010, Pages 547-555

https://doi.org/10.1016/j.tibs.2010.04.005 Get rights and content

O-linked β-N-acetylglucosamine (O-GlcNAc) is a sugar attachment to serine or threonine hydroxyl moieties on nuclear and cytoplasmic proteins. In many ways, O-GlcNAcylation is similar to phosphorylation because both post-translational modifications cycle rapidly in response to internal or environmental cues. O-GlcNAcylated proteins are involved in transcription, translation, cytoskeletal assembly, signal transduction, and many other cellular functions. O-GlcNAc signaling is intertwined with cellular metabolism; indeed, the donor sugar for O-GlcNAcylation (UDP-GlcNAc) is synthesized from glucose, glutamine, and UTP via the hexosamine biosynthetic pathway. Emerging research indicates that O-GlcNAc signaling and its crosstalk with phosphorylation are altered in metabolic diseases, such as diabetes and cancer.

Section snippets

O-GlcNAc: a metabolic signaling molecule

One of the most pressing medical issues facing industrialized countries is the rapid rise of type 2 diabetes, a metabolic disorder characterized by severely elevated blood glucose and insensitivity to insulin. In the United States alone, 7.8% of the population is diagnosed with diabetes, and up to 57 million Americans have pre-diabetes. The cost for treating type 2 diabetes was $174 billion in 2007, and consumed 32% of Medicare spending (http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf).

Nutrient flux through the hexosamine biosynthetic pathway (HBP)

The HBP integrates a variety of metabolic inputs in the synthesis of UDP-GlcNAc (Figure 1). First, approximately 2–3% of total cellular glucose is funneled into the HBP 5, 10, 11, although the glucose flux is potentially different in various cell types and we know little about the regulation of the flux of glucose into the HBP. The HBP shares its first two steps with glycolysis; first, hexokinase phosphorylates glucose to produce glucose 6-phosphate, which is then converted into fructose

O-GlcNAc signaling in a diabetic background

In normal liver cells exposed to insulin, a complex signal transduction cascade is initiated resulting in altered gene expression and the translocation of the insulin responsive glucose transporter GLUT4 to the plasma membrane [29]. Insulin binds to the insulin receptor causing the receptor to autophosphorylate, which recruits the insulin receptor substrate (IRS1 or IRS2) [29]. IRS is phosphorylated at multiple tyrosine residues, activating the docking of the phosphatidylinositol 3-kinase

O-GlcNAc transferase regulates insulin signaling

Studies from several laboratories suggest that O-GlcNAcylation plays a direct role in insulin signaling (for reviews see Refs 1, 3, 10). Under normal cellular conditions, OGT is localized to the nucleus and the perinuclear region with only moderate staining observed in the cytoplasm [37]. However, upon insulin stimulation a subset of OGT translocates to the plasma membrane 38, 39, mediated by a non-canonical PIP3 binding domain on the OGT carboxy-terminus [38]. At the membrane, OGT associates

The influence of cancer on the HBP

A physiological hallmark of tumors is the use of aerobic glycolysis (also known as the Warburg effect) instead of oxidative phosphorylation to produce ATP [48]. Aerobic glycolysis is a normal function of rapidly proliferating cells which provides both bioenergetic and biosynthetic needs 49, 50. Herein, we will discuss aerobic glycolysis and how it influences the HBP, and how disruption of the HBP alters O-GlcNAcylation. Aerobic glycolysis is characterized by the conversion of glucose into

O-GlcNAcylation of oncogenes and tumor suppressors

c-Myc is a transcription factor whose expression increases in proliferative cells and regulates genes involved in glycolysis, purine/pyrimidine, and lipid metabolism 59, 60, as well as genes involved in glutamine metabolism, mitochondria biosynthesis, cell cycle control, and HBP genes 60, 61. c-Myc is O-GlcNAcylated [62] at threonine 58, which is also a GSK3β phosphorylation site [7]. GSK3β requires a priming phosphorylation site before it can actively phosphorylate most substrates; in the case

Promoting aneuploidy through O-GlcNAc

A common phenotype in cancer cells is aneuploidy (abnormal number of chromosomes), which promotes tumorigenesis [70]. Whereas partial loss of mitotic checkpoint control causes low levels of aneuploidy, complete loss of checkpoint control causes massive aneuploidy and cell death [70]. Over-expression of OGT by only two-fold promotes aneuploidy through disruptions in mitotic progression [34]. Normally, during M phase, a subset of OGT localizes to the mitotic spindle, which then moves through the

Concluding remarks and future perspectives

Obviously, diseases such as diabetes and cancer are increasingly becoming major health risks to industrialized countries. Both diseases present major alterations in metabolism, which will impinge upon and alter O-GlcNAcylation. These alterations to O-GlcNAcylation disrupt cellular signaling cascades and potentially promote the disease state. Understanding the molecular mechanisms in common between these two diseases will provide opportunities for improved treatment. Because aberrant O-GlcNAc

Acknowledgments

We thank the members of the Hart laboratory for critical reading of the manuscript. Research is supported by the National Institutes of Health (R01 DK61671 and R01 CA42486 to G.W.H).

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Trends in Biochemical Sciences

ReviewO-GlcNAc signaling: a metabolic link between diabetes and cancer?

Section snippets

O-GlcNAc: a metabolic signaling molecule

Nutrient flux through the hexosamine biosynthetic pathway (HBP)

O-GlcNAc signaling in a diabetic background

O-GlcNAc transferase regulates insulin signaling

The influence of cancer on the HBP

O-GlcNAcylation of oncogenes and tumor suppressors

Promoting aneuploidy through O-GlcNAc

Concluding remarks and future perspectives

Acknowledgments

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Review
O-GlcNAc signaling: a metabolic link between diabetes and cancer?