O-GlcNAcylation in Cancer Biology: Linking Metabolism and Signaling

Abstract

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.

Keywords: O-GlcNAcylation; OGT; cancer; glycosylation; signaling.

Figure 1. The Hexosamine Pathway Intersects with the Receptor Tyrosine Kinase/AMPK/mTOR Pathway

In left panel, the hexosamine pathway controls O-GlcNAcylation of nuclear and cytoplasmic proteins. A small fraction (2-5%) of glucose enters the HBP and fructose-6-phosphate is converted to glucosamine-6-phosphate by the rate-limiting enzyme of this pathway glutamine:fructose-6- amidotransferase (GFAT). UDP-N-acetylglucosamine (UDP-GlcNAc) is generated in subsequent steps and used as substrate by O-GlcNAc transferase (OGT) to add GlcNAc to serine or threonine residues of nuclear or cytoplasmic target proteins. O-GlcNAc modifications can be removed from proteins by the glycoside hydrolase O-GlcNAcase (OGA). In right panel, the receptor tyrosine kinase (RTK)-mediated signaling pathways converge on mTOR to regulate key transcription factors involved in cancer metabolism including HIF-1α, c-MYC, and SREBP-1. LKB1/AMPK negatively regulate mTOR pathway and metabolism. OGT and O-GlcNAcylation can intersect with this pathway at level of AMPK and regulation of key metabolic transcription factors HIF-1α and c-Myc. Abbreviations: HK2, hexokinase, PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3; PDK1, pyruvate dehydrogenase kinase, isozyme 1; PGK, phosphoglycerate kinase; PKM2, pyruvate kinase M2 isoform; LDHA, lactate dehydrogenase A; GLS1, glutaminae 1; ACLY, ATP citrate lyase; FASN, fatty acid synthase; ACC1, acetyl-CoA carboxylase 1.

Figure 2. OGT and O-GlcNAcylation Regulate Multiple “Hallmarks of Cancer”

OGT via O-GlcNAcylation directly or indirectly regulate proteins that play major role in regulating multiple cancer phenotypes.