Decoding the Hexosamine Biosynthesis Pathway: Implications for Novel Therapeutic Strategies in Sarcoma

Cancer cells rewire their metabolism to sustain a high proliferation rate. Sensing external cues is essential to match the metabolic fluxes of the cells to the external stimuli. As part of the glucose metabolism, the hexosamine biosynthesis pathway (HBP) is considered a nutrient-sensing pathway. The HBP produces UDP-GlcNAc, a key precursor for N-linked glycosylation, O-linked glycosylation, and O-GlcNAcylation. These post-translational modifications can influence protein folding, interactions, and subcellular localization. Altered glycosylation of oncogenic proteins has been linked to the acquisition of malignant properties. In this review, we outline the current knowledge of molecular alterations and the prognostic role of the expression of HBP enzymes in sarcoma. We catalog the known sites of N-/O-linked glycosylation and O-GlcNAc modifications in molecular drivers of mesenchymal tumors, and discuss the potential effect of these modifications on protein function. We also summarize the studies that examined the effect of the HBP inhibitors in preclinical models of cancer, and explore the potential of the HBP inhibition as a novel therapeutic approach for sarcoma. Finally, we present recent progress in drug development for targeting the HBP, and delineate the key technological innovations needed to accelerate the preclinical and clinical research on pharmacological inhibition of the HBP.