Abstract
Simple SummaryO-linked β-N-acetylglucosamine (O-GlcNAc) is a post-translational modification (PTM) linking nutrient flux through the hexosamine biosynthetic pathway (HBP) to gene transcription. Mounting experimental and clinical data implicates aberrant O-GlcNAcylation in the development and progression of cancer. Herein, we discuss how alteration of O-GlcNAc-regulated transcriptional mechanisms leads to atypical gene expression in cancer. We discuss the challenges associated with studying O-GlcNAc function and present several new approaches for studies of O-GlcNAc-regulated transcription.O-linked β-N-acetylglucosamine (O-GlcNAc) is a single sugar post-translational modification (PTM) of intracellular proteins linking nutrient flux through the Hexosamine Biosynthetic Pathway (HBP) to the control of cis-regulatory elements in the genome. Aberrant O-GlcNAcylation is associated with the development, progression, and alterations in gene expression in cancer. O-GlcNAc cycling is defined as the addition and subsequent removal of the modification by O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA) provides a novel method for cells to regulate various aspects of gene expression, including RNA polymerase function, epigenetic dynamics, and transcription factor activity. We will focus on the complex relationship between phosphorylation and O-GlcNAcylation in the regulation of the RNA Polymerase II (RNAP II) pre-initiation complex and the regulation of the carboxyl-terminal domain of RNAP II via the synchronous actions of OGT, OGA, and kinases. Additionally, we discuss how O-GlcNAcylation of TATA-box binding protein (TBP) alters cellular metabolism. Next, in a non-exhaustive manner, we will discuss the current literature on how O-GlcNAcylation drives gene transcription in cancer through changes in transcription factor or chromatin remodeling complex functions. We conclude with a discussion of the challenges associated with studying O-GlcNAcylation and present several new approaches for studying O-GlcNAc regulated transcription that will advance our understanding of the role of O-GlcNAc in cancer.
Highlights
Simple Summary: O-linked β-N-acetylglucosamine (O-GlcNAc) is a post-translational modification (PTM) linking nutrient flux through the hexosamine biosynthetic pathway (HBP) to gene transcription
The metabolic reprogramming mechanism presented by Hardiville et al [43] may be involved with cancer pathology, but the question remains whether aberrant O-GlcNAcylation is a driver or a consequence of upstream events that led to the manifestation of cancer
Methylation of cytosines in DNA, at promoter CpG islands, is the classical epigenetic modification that plays a critical role in transcription, affecting such downstream processes as chromosome accessibility, nucleosome positioning, and gene expression [57]
Summary
Changes in intracellular nutrient metabolite pools directly affect the level uridinediphosphate N-acetyl glucosamine (UDP-GlcNAc), the substrate for OGT and other glycosyltransferases, produced by the HBP [17,18]. The HBP utilizes products from amino acid, fatty acid, nucleotide, and glucose metabolism to generate UDP-GlcNAc. Since multiple metabolites feed into the HBP, UDP-GlcNAc levels are responsive to fluctuations in these metabolic pathways (Figure 1) [19,20,21]. Increasing glucose availability induces a rapid increase in intracellular UDP-GlcNAc levels in a variety of cell types [22,23,24,25]. Similar to Cancers 2021, 13, 1666 glucose, changes in the intracellular glutamine, fatty acid, and nucleotide pools lead to a modulation of HBP flux and UDP-GlcNAc levels [17]. O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) facilitate O-GlcNAc cycling “on and off” serine and threonine amino acid residues of target proteins
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