Mini-reviewO-GlcNAc signaling in cancer metabolism and epigenetics
Introduction
In the United States, it has been estimated that half of all men and one third of all women will suffer from cancer during their lifetime. The transition of normal cells to cancer cells is marked by a series of genetic and epigenetic changes associated with chromosomal instability, oncogene activation, tumor suppressor functions, gene silencing, and DNA repair deficiency. Epigenetic reprogramming, including alterations in DNA methylation and histone modifications, drives tumorigenesis by altering chromosomal structure and gene expression [11], [31], [39], [52]. Epigenetic DNA modifications such as global hypomethylation and tumor suppressor specific hypermethylation in CpG-rich regions have been observed in multiple types of cancer cells [98]. Gene-specific alterations in histone modifications, loss of histone H4 acetylation and trimethylation has frequently been observed in cancer cells [9], [11], [31].
Among the most distinguished hallmarks of cancer, metabolic rewiring is characterized by increased glucose uptake and aerobic glycolysis to facilitate rapid cell growth and proliferation [116], [117]. Metabolic rewiring is closely associated with epigenetic reprogramming, which can be influenced by environmental factors, such as diet [65] and genetic defects in metabolic enzymes [2], [7], [24], [29], [57], [58], [89], [111]. Mounting evidence has shown that epigenetics can contribute to reprogramming of cancer metabolism by modulating gene expression [20], [56], [120], [123].
O-GlcNAcylation is a posttranslational modification by O-linked β-N-acetylglucosamine (O-GlcNAc) moiety at serine or threonine residues of proteins [40], [41], [110]. Similar to other posttranslational modifications such as phosphorylation and acetylation, O-GlcNAc can modify a wide spectrum of intracellular proteins, including signaling proteins, transcription factors, metabolic enzymes, and histones, through which it regulates crucial cellular processes, such as signal transduction, transcription, translation, and protein degradation [34], [40], [41], [122], [123], [124], [125], [128]. Cellular O-GlcNAc levels are linked to both physiological and disease conditions. A growing body of evidence reveals its relevance to diabetes, cancer, neurodegenerative disease, and cardiovascular disease [22], [26], [30], [94], [126]. As reviewed elegantly elsewhere [32], aberrant O-GlcNAcylation has been observed in a wide range of cancer types, and a regulatory role of O-GlcNAcylation in cancer has begun to be uncovered (Table 1).
Yet unlike the cycling of phosphorylation, which involves 428 serine/threonine kinase and ∼40 phosphatases [4], [76], the cycling of O-GlcNAcylation depends merely on two opposing enzymes: O-linked β-N-acetylglucosamine transferase (OGT) catalyzes the addition of the sugar moiety to the protein and O-GlcNAcase (OGA, NCOAT, or MGEA5) catalyzes the sugar removal. O-GlcNAc modification dynamically responds to environmental and physiological cues, among which nutrient availability is vital. Cellular O-GlcNAcylation levels can fluctuate in response to the availability of nutrients such as glucose, free fatty acid, uridine, and glutamine, endowing this modification with the unique property as a nutrient sensor [13], [32], [40], [67], [118], [127]. The addition of the O-GlcNAc moiety requires the high-energy molecule UDP-GlcNAc, as the donor substrate. UDP-GlcNAc is a major end product of hexosamine biosynthesis pathway (HBP), which is fed by nutrient flux into the cell. In this regard, the cellular O-GlcNAcylation level is believed to reflect on systemic metabolic status (Fig. 1).
The role of O-GlcNAc modification in epigenetics has emerged as a topic of interest. OGT and OGA can target histones and enzymes involved in epigenetic modifications, which could potentially influence gene expression. O-GlcNAc can serve as the link between nutrient availability and epigenetics, as epigenetic modifications also require nutrient derived metabolites as substrates. In this review, we summarize the current understanding of the role of O-GlcNAc at the interface of cancer metabolism and epigenetics.
Section snippets
O-GlcNAcylation of signaling proteins
In analogy to phosphorylation, O-GlcNAcylation is a regulatory mechanism that modifies cellular proteins at serine and threonine residues in response to stress, hormones and nutrients. Crosstalk between O-GlcNAcylation and phosphorylation has been implicated in regulation of signal transduction in cancer [44], [107]. Direct O-GlcNAcylation of kinases and phosphatases may contribute to cancer phenotypes. Akt Ser 473 undergoes both phosphorylation and O-GlcNAcylation in murine pancreatic β cells,
The epigenetic code
Genetic and epigenetic regulation is essential for life. Cancer arises from a combination of changes to the genome and the epigenome [10]. An epigenome is defined as the complete set of DNA methylation and posttranslational modifications of histone proteins [5], [12]. These covalent modifications alter chromatin structure and regulate gene expression [9], [59]. Histones can be posttranslationally modified by phosphorylation, acetylation, succinylation, malonylation, methylation, and
Conclusions
Posttranslational modifications are a major toolbox in cell physiology. Availability of metabolites, such as UDP-GlcNAc, acetyl-CoA and ATP, is essential for O-GlcNAcylation, acetylation and phosphorylation respectively. Combinatorial changes in different posttranslational modifications, referred to as the “PTM code”, dictate protein activity and ultimately influence metabolic homeostasis (Fig. 2). Cancer cells appear to alter HBP flux and O-GlcNAcylation to reprogram metabolism in favor of
Acknowledgements
We thank all members of the Yang laboratory for stimulating discussions. This work was supported by NIH R01 DK089098, P01 DK057751, and Yale Comprehensive Cancer Center Pilot Grant to X.Y.
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