Journal of Molecular Biology

Journal of Molecular Biology

Volume 428, Issue 16, 14 August 2016, Pages 3282-3294
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Review
O-GlcNAcylation in Cancer Biology: Linking Metabolism and Signaling

https://doi.org/10.1016/j.jmb.2016.05.028Get rights and content

Highlights

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    O-GlcNAcylation levels are found elevated in nearly all cancers examined.

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    O-GlcNAc cycling enzymes O-GlcNAc transferase and O-GlcNAcase are altered in many cancers.

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    O-GlcNAcylation regulates many aspects of the “Hallmarks of Cancer”.

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    Reducing O-GlcNAcylation in cancer cells may be a potential treatment strategy.

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.

Section snippets

Linking Cellular Signaling Pathways to Metabolic Rewiring in Cancer

Cancer cells universally promote glycolysis in the presence of normal oxygen conditions [1], [2]. This altered metabolic state, known as the Warburg effect, allows cancer cells to take up a large share of nutrients from their environment (i.e., glucose and glutamine), a phenomenon that is widely used in vivo to monitor tumor growth using 2FDG-PET imaging [1], [2]. As a by-product of the inefficient use of these nutrients, low amounts of ATP are produced, and sizeable amounts of carbon and

Hexosamine Biosynthetic Pathway Regulates Metabolism, Signaling, and Cancer

The capacity to sense nutrients in the cellular environment is a crucial evolutionary mechanism required for adaptation and survival [5]. In proliferating cells, glucose and glutamine consumption are regulated via growth factor signaling to support cell growth and survival. However, cancer cells, independent of growth factor stimulation, can utilize glucose- and glutamine-derived carbon sources to fuel ATP synthesis and support cell growth [5]. While the majority of glucose molecules that enter

O-GlcNAc Enzymes and O-GlcNAcylation in Cancer

Many cancer types display elevated O-GlcNAcylation and aberrant expression of OGT and OGA (Table 1) [32], [33]. For example, multiple studies demonstrate that breast cancer cell lines and patient samples contain elevated levels of OGT and O-GlcNAc compared to normal counterparts [34], [35], [36], [37], [38]. More recently, our lab demonstrated that within breast cancer subtypes, aggressive basal-like tumors contain high levels of OGT and O-GlcNAc compared to luminal-type breast cancers [39].

Mechanisms of OGT elevation in cancer

Although the levels of UDP-GlcNAc within the various cellular compartments exquisitely regulate the affinity of OGT for peptide substrates, little is known about the mechanisms of OGT regulation in cancer. Recent reports have demonstrated that oncogenic pathway activation mediates increases in OGT and overall O-GlcNAcylation in various cancer cells [47], [55], [56].

Sodi et al. recently demonstrated that the PI3K-mTOR-MYC signaling pathway is required for the elevation of OGT and O-GlcNAcylation

The role of O-GlcNAc Cycling Enzymes in the Regulation of Cancer Hallmarks

Studies in the past five years have implicated OGT and O-GlcNAcylation as regulators of many cancer phenotypes including multiple “Hallmarks of Cancer” [58] (Fig. 2). Below, we summarize recent studies that implicate OGT and O-GlcNAcylation directly and/or indirectly in the regulation of various cancer phenotypes.

O-GlcNAc Transferase as a Therapeutic Target in Cancer

Various studies demonstrate a therapeutic window that may exist to specifically target OGT and O-GlcNAcylation in cancer cells [39], [40], [80]. A number of novel chemicals have been developed to target OGT and reduce O-GlcNAcylation in mammalian cells; namely, small molecule OGT inhibitors [81] and UDP-GlcNAc salvage pathway analogs [29]. In the past 10 years, Walker and colleagues [81], [82] have developed a number of OGT inhibitors aimed at providing insights to the biological and structural

Emerging Roles for O-GlcNAcylation

Cancer is a disease associated with aging [89], and a number of studies suggest a role for OGT in aging. Recent data show that total levels of O-GlcNAcylation are elevated in aging tissue [90]. Major areas of interest in the field of aging, including autophagy and the sirtuins, appear to have links to OGT and O-GlcNAcylation.

Changes in autophagy have a cause-and-effect role in the process of aging [91]. Often, autophagy is enhanced by interventions shown to extend lifespan. These include

Implications and Future Directions

Research into the evolving role of O-GlcNAcylation in normal biology and pathologies will continue to expand our understanding of the role of this modification in disease states such as cancer. Although there is ample evidence for a role of OGT in many “Hallmarks of Cancer” (Fig. 2), there is still little evidence that OGT or O-GlcNAcylation may play a role in enabling replicative immortality or avoiding immune destruction. We must continue to expand our insight into the roles of OGT and

Acknowledgments

This work is supported by NIH-NCI grants CA183574 (to C.M.F.), CA192868 (to V.L.S.), and CA155413 (to M.J.R.).

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