O-GlcNAc signaling in cancer metabolism and epigenetics

Abstract

The covalent attachment of β-D-N-acetylglucosamine monosaccharides (O-GlcNAc) to serine/threonine residues of nuclear and cytoplasmic proteins is a major regulatory mechanism in cell physiology. Aberrant O-GlcNAc modification of signaling proteins, metabolic enzymes, and transcriptional and epigenetic regulators has been implicated in cancer. Relentless growth of cancer cells requires metabolic reprogramming that is intertwined with changes in the epigenetic landscape. This review highlights the emerging role of protein O-GlcNAcylation at the interface of cancer metabolism and epigenetics.

Keywords: Cancer metabolism; Epigenetics; O-GlcNAc; Posttranslational modifications.

Figure 1. Hexosamine biosynthetic pathway targets protein O-GlcNAc modification

Glucose (Glc) uptaken by cells is mainly used in glycogen synthesis and glycolysis pathways. 2~5% of glucose fluxes into hexosamine pathway through the conversion of fructose-6-phosphate (Fru-6P) to glucosamine-6-phosphate (GlcN-6P) by a rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase (GFAT). Subsequent acetylation and uridylation of GlcN-6P produce UDP-GlcNAc as a substrate for protein glycosylation. O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) catalyze the addition and removal of O-GlcNAc on proteins, respectively.

Figure 2. Nutritional and hormonal regulation of metabolism through the “PTM code”

External hormonal and nutritional cues modulate intracellular fluctuation of ATP/AMP, UDP-GlcNAc, Acetyl-CoA and NAD+ levels. These metabolites influence phosphorylation, O-GlcNAcylation, and acetylation of a wide variety of intracellular proteins such as signaling proteins, metabolic enzymes, transcriptional factors/cofactors and histones. Combinatorial changes in these posttranslational modifications may constitute the “PTM code” that integrates environmental cues to regulate metabolic homeostasis. Alteration of the “PTM code” by carcinogens may be central to metabolic and epigenetic reprogramming in cancer.

Figure 3. OGT is associated with multiple epigenetic modifications

OGT interacts with the HCF-1/TET complex that mediates DNA demethylation, the HCF-1/BAP1 complex that mediates histone deubiquitination, the HCF-1/HNMT complex that mediates histone methylation, and the Sin3A/HDAC complex that mediates histone deacetylation. OGT directly modifies histones through unknown adaptor proteins.