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Fig. 4 | BMC Biology

Fig. 4

From: Fueling the fire: emerging role of the hexosamine biosynthetic pathway in cancer

Fig. 4

The HBP regulates multiple proteins in cancer cells via OGT. Increased glucose uptake increases HBP flux, leading to elevated UDP-GlcNAc levels and increased O-GlcNAcylation via enzymatic activity of O-GlcNAc transferase (OGT) that can positively (green) or negatively (red) regulate protein function. Increased HBP flux reduces AMPK activity and its phosphorylation of SREBP1, thus regulating lipid biogenesis. AMPK can phosphorylate GFAT and reduce HBP flux (in normal cells). O-GlcNAc modifications of transcription factors c-myc, YAP, and NF-kB result in their activation, which promotes tumorigenesis by activation of glycolytic, fatty acid synthesis, and stress survival genes while blocking expression of apoptotic genes. Elevated O-GlcNAcylation disrupts the interaction between HIF-1and von Hippel-Lindau protein (pVHL), resulting in activation of HIF-1, which upregulates GLUT1 levels and glycolytic enzymes, and increases stress survival. SNAIL O-GlcNAc modification leads to reduced levels of E-cadherin, which can be N-glycosylated upon elevated UDP-GlcNAc levels promoting EMT activation and invasive properties. The addition of a GlcNAc (G) moiety inhibits PFK1 activity, increasing flux into the PPP. Fumarase (FH) interaction with ATF2 is blocked upon its O-GlcNAc modification, resulting in failure to activate cell arrest. O-GlcNAcylation of FOXO3 and H2AX can block their function and contribute to cell growth and block DNA repair, respectively. O-GlcNAcylation of RRMI can destabilize the ribonucleotide reductase complex and cause replication stress and DNA damage

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