Abstract
The hexosamine biosynthetic pathway (HBP) integrates glucose, amino acids, fatty acids and nucleotides metabolisms for uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis. UDP-GlcNAc is the nucleotide sugar donor for O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) processes. O-GlcNAc transferase (OGT) is the enzyme which transfers the N-acetylglucosamine (O-GlcNAc) residue onto target proteins. Several studies previously showed that glucose metabolism dysregulations associated with obesity, diabetes or cancer correlated with an increase of OGT expression and global O-GlcNAcylation levels. Moreover, these diseases present an increased activation of the nutrient sensing mammalian target of rapamycin (mTOR) pathway. Other works demonstrate that mTOR regulates protein O-GlcNAcylation in cancer cells through stabilization of OGT. In this context, we studied the cross-talk between these two metabolic sensors in vivo in obese mice predisposed to diabetes and in vitro in normal and colon cancer cells. We report that levels of OGT and O-GlcNAcylation are increased in obese mice colon tissues and colon cancer cells and are associated with a higher activation of mTOR signaling. In parallel, treatments with mTOR regulators modulate OGT and O-GlcNAcylation levels in both normal and colon cancer cells. However, deregulation of O-GlcNAcylation affects mTOR signaling activation only in cancer cells. Thus, a crosstalk exists between O-GlcNAcylation and mTOR signaling in contexts of metabolism dysregulation associated to obesity or cancer.
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Acknowledgements
This work was supported by the “Ligue Contre le Cancer/Comité du Nord” the “Fondation ARC (Association pour la Recherche sur le Cancer),” the Région Nord-Pas de Calais (Cancer Regional Program), the University of Lille and the “Centre National de la Recherche Scientifique”. The authors are also grateful to the “SIte de Recherche Intégré sur le Cancer” (SIRIC) ONCOLille and to FR 3688 FRABio. N.V. is the recipient of a fellowship from the “Ministère de l'Enseignement Supérieur et de la Recherche”.
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Very, N., Steenackers, A., Dubuquoy, C. et al. Cross regulation between mTOR signaling and O-GlcNAcylation. J Bioenerg Biomembr 50, 213–222 (2018). https://doi.org/10.1007/s10863-018-9747-y
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DOI: https://doi.org/10.1007/s10863-018-9747-y