Abstract
In the past decade, aberrant O-GlcNAcylation has emerged as a new hallmark of cancer. O-GlcNAcylation is a post-translational modification that results when the amino-sugar β-D-N-acetylglucosamine (GlcNAc) is made in the hexosamine biosynthesis pathway (HBP) and covalently attached to serine and threonine residues in intracellular proteins by the glycosyltransferase O-GlcNAc transferase (OGT). O-GlcNAc moieties reflect the metabolic state of a cell and are removed by O-GlcNAcase (OGA). O-GlcNAcylation affects signaling pathways and protein expression by cross-talk with kinases and proteasomes and changes gene expression by altering protein interactions, localization, and complex formation. The HBP and O-GlcNAcylation are also recognized to mediate survival of cells in harsh conditions. Consequently, O-GlcNAcylation can affect many of the cellular processes that are relevant for cancer and is generally thought to promote tumor growth, disease progression, and immune escape. However, recent studies suggest a more nuanced view with O-GlcNAcylation acting as a tumor promoter or suppressor depending on the stage of disease or the genetic abnormalities, proliferative status, and state of the p53 axis in the cancer cell. Clinically relevant HBP and OGA inhibitors are already available and OGT inhibitors are in development to modulate O-GlcNAcylation as a potentially novel cancer treatment. Here recent studies that implicate O-GlcNAcylation in oncogenic properties of blood cancers are reviewed, focusing on chronic lymphocytic leukemia and effects on signal transduction and stress resistance in the cancer microenvironment. Therapeutic strategies for targeting the HBP and O-GlcNAcylation are also discussed.
Highlights
Upon entry into a cell, glucose is phosphorylated to fructose-6-phosphate before continuing down the glycolysis pathway
About 2-5% of fructose-6-phosphate is normally diverted into the hexosamine biosynthetic pathway (HBP) (Figure 1), a minor metabolic pathway increasingly recognized to have an important role in cancer biology [1]
Acetyl-CoA is added by GlcN-6-phosphate acetyl transferase (GNAT) to make N-acetyl glucosamine (GlcNAc)-6-phosphate, which is rearranged to GlcNAc-1phosphate by GlcNAc-phosphoglucomutase (AGM)
Summary
Upon entry into a cell, glucose is phosphorylated to fructose-6-phosphate before continuing down the glycolysis pathway. UDP-GlcNAc is involved in glycosylation of cell-surface lipids and proteins [2] and employed by O-linked GlcNAc transferase (OGT) to O-GlcNAcylate serine and threonine residues on intracellular proteins. These modifications can be removed by the deglycosylating enzyme, O-GlcNAcase (OGA) encoded by OGA, formerly known as MGEA5 [2, 3] (Figure 1). Serine and threonine targets of OGT may be phosphorylation sites that are blocked by OGlcNAc residues to disturb signaling pathways [1]. Changes in OGlcNAcylation from altered metabolism or stress can dysregulate cell signaling networks [1, 14]. Studies about OGlcNAcylation in other blood cancers are reviewed
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