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Review
. 2018 Jun 2;7(6):53.
doi: 10.3390/cells7060053.

The Nutrient-Sensing Hexosamine Biosynthetic Pathway as the Hub of Cancer Metabolic Rewiring

Ferdinando Chiaradonna  1 , Francesca Ricciardiello  2 , Roberta Palorini  3
Affiliations
Review

The Nutrient-Sensing Hexosamine Biosynthetic Pathway as the Hub of Cancer Metabolic Rewiring

Ferdinando Chiaradonna et al. Cells. .

Abstract

Alterations in glucose and glutamine utilizing pathways and in fatty acid metabolism are currently considered the most significant and prevalent metabolic changes observed in almost all types of tumors. Glucose, glutamine and fatty acids are the substrates for the hexosamine biosynthetic pathway (HBP). This metabolic pathway generates the "sensing molecule" UDP-N-Acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is the substrate for the enzymes involved in protein N- and O-glycosylation, two important post-translational modifications (PTMs) identified in several proteins localized in the extracellular space, on the cell membrane and in the cytoplasm, nucleus and mitochondria. Since protein glycosylation controls several key aspects of cell physiology, aberrant protein glycosylation has been associated with different human diseases, including cancer. Here we review recent evidence indicating the tight association between the HBP flux and cell metabolism, with particular emphasis on the post-transcriptional and transcriptional mechanisms regulated by the HBP that may cause the metabolic rewiring observed in cancer. We describe the implications of both protein O- and N-glycosylation in cancer cell metabolism and bioenergetics; focusing our attention on the effect of these PTMs on nutrient transport and on the transcriptional regulation and function of cancer-specific metabolic pathways.

Keywords: UDP-GlcNAc; bioenergetics; cancer; hexosamine biosynthesis pathway; metabolism; protein glycosylation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the hexosamine biosynthesis pathway. HBP enzymes are depicted in red, metabolites in black, cellular processes in light blue. The green/red boxes indicate the metabolites whose change induces UDP-GlcNAc decrease (green) or increase (red).
Figure 2
Figure 2
Schematic representation of the nutrient transporters discussed in the text. The arrows in the transporters indicate the direction of the flux. The red arrows indicate the increased nutrient transport and/or transporter affinity/targeting/stability. The single or double symbol of N-glycosylation indicates low or high glycosylated protein, respectively. The cartoon representing endoplasmic reticulum and Golgi indicates stability and targeting. Gluc: glucose; Lac: lactate; Gln: glutamine; AA: amino acid; l-Car: l-carnitine.
Figure 3
Figure 3
HBP modulates cancer metabolism through the O-GlcNAcylation of metabolic enzymes, signaling proteins and mitochondrial proteins. (A) In the image, the main metabolic pathways exploited by cancer cells for anabolism and bioenergetics are represented. The O-GlcNAcylated proteins (mainly the metabolic enzymes) are indicated in the grey boxes if the effect of the glycosylation has been demonstrated. The circle on the box, representing the O-GlcNAcylation, is red when the protein function is activated by glycosylation and green when it is inhibited. (B) The reciprocal regulation of AMPK and PKA and the HBP is schematically represented as discussed in the main text. 6-PG, 6-phosphogluconate; 3-PG, 3-phosphoglycerate; PEP, phosphoenolpyruvate; THF, tetrahydrofolate; DHF, dihydrofolate; FA, fatty acids; Fatty Ac-CoA, Fatty Acyl-Coenzyme A; GSH, glutathione; Trx, thioredoxin; NT, nucleotides.
Figure 4
Figure 4
Schematic representation of the main metabolic pathways influenced (positively and/or negatively) by transcriptional factor O-GlcNAcylation. The figure depicts, from a schematic point of view, the transcriptional factors whose stability, transcriptional activation, DNA binding ability and protein–protein interaction is regulated by direct O-GlcNAcylation and the metabolic pathways influenced by their O-GlcNAcylation. The colored square around the indicated metabolic pathways is related to the specific transcriptional factor that upon O-GlcNAcylation is able to control the pathway.
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