O-GlcNAcylation in Cancer Biology: Linking Metabolism and Signaling

The hexosamine biosynthetic pathway (HBP) is highly dependent on multiple metabolic nutrients including glucose, glutamine, and acetyl-CoA. Increased flux through HBP leads to elevated post-translational addition of β-D-N-acetylglucosamine sugars to nuclear and cytoplasmic proteins. Increased total O-GlcNAcylation is emerging as a general characteristic of cancer cells, and recent studies suggest that O-GlcNAcylation is a central communicator of nutritional status to control key signaling and metabolic pathways that regulate multiple cancer cell phenotypes. This review summarizes our current understanding of changes of O-GlcNAc cycling enzymes in cancer, the role of O-GlcNAcylation in tumorigenesis, and the current challenges in targeting this pathway therapeutically. [Display omitted] •O-GlcNAcylation levels are found elevated in nearly all cancers examined.•O-GlcNAc cycling enzymes O-GlcNAc transferase and O-GlcNAcase are altered in many cancers.•O-GlcNAcylation regulates many aspects of the “Hallmarks of Cancer”.•Reducing O-GlcNAcylation in cancer cells may be a potential treatment strategy.