O-GlcNAc signalling: implications for cancer cell biology - PubMed (original) (raw)

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O-GlcNAc signalling: implications for cancer cell biology

Chad Slawson et al. Nat Rev Cancer. 2011.

Abstract

O-GlcNAcylation is the covalent attachment of β-D-N-acetylglucosamine (GlcNAc) sugars to serine or threonine residues of nuclear and cytoplasmic proteins, and it is involved in extensive crosstalk with other post-translational modifications, such as phosphorylation. O-GlcNAcylation is becoming increasing realized as having important roles in cancer-relevant processes, such as cell signalling, transcription, cell division, metabolism and cytoskeletal regulation. However, currently little is known about the specific roles of aberrant O-GlcNAcylation in cancer. In this Opinion article, we summarize the current understanding of O-GlcNAcylation in cancer and its emerging functions in transcriptional regulation at the level of chromatin and transcription factors.

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Figures

Figure 1

Figure 1. _O_-GlcNAc modifies the transcriptional machinery

In this inverted pyramid diagram, the transcription-regulating proteins that are modified by β-D-_N_-acetylglucosamine (GlcNAc; G) are shown. In addition to its catalytic role, _O_-linked _N_-acetylglucosamine transferase (OGT; red ovals) interacts with numerous transcription-regulating proteins. Starting from the bottom, histones are dynamically modified by _O_-GlcNAc; furthermore, the carboxy-terminal domain of RNA polymerase II (RNA Pol II), as well as the basal transcription factors (purple ovals) are also modified by _O_-GlcNAc. Many of the transcription-activating and transcription-repressing complexes (yellow circles) that contain histone-modifying enzymes, such as histone methyltransferases, histone acetytransferases and histone deacetylases, also interact with OGT, suggesting that OGT is an integral unit in the regulation of the histone code. Finally, many transcription factors (light blue circles) are modified by _O_-GlcNAc. Together, the collected data from many laboratories have strongly confirmed the regulation of gene transcription by _O_-GlcNAcylation. CEBPβ, CCAAT/enhancer-binding protein-β; CREB1, cyclicAMP-responsive element-binding protein 1; CRTC2, CREB-regulated transcription coactivator 2; FOXO, forkhead box protein O family; HCF1, host cell factor 1; MSL, male-specific lethal; NFAT, nuclear factor of activated T cells; NSL, nonspecific lethal; PDX1, pancreas/duodenum homeobox protein 1; PGC1α: peroxisome proliferator-activated receptor-γ co-activator 1α; PH, Polyhomeotic protein; TBP, TATA-box-binding protein.

Figure 2

Figure 2. Histone _O_-GlcNAcylation increases after stress

After a cellular stress event, histone _O_-GlcNAcylation (the covalent attachment of β-D-_N_-acetylglucosamine (GlcNAc) sugars to serine or threonine residues of proteins; green dots) increases, and this is correlated with an increase in DNA compaction. Histone _O_-GlcNAcylation is catalysed by _O_-GlcNAc transferase (OGT) via the addition of a GlcNAc moiety from UDP-GlcNAc.

Figure 3

Figure 3. Regulation of transcription factors by _O_-GlcNAc

a | The tumour suppressor p53 associates with the protein MDM2, which keeps p53 at low levels in cells by promoting its degradation. Phosphorylation (P) at Thr155 stimulates the rapid degradation of p53, and _O_-GlcNAcylation (the covalent attachment of β-D-_N_-acetylglucosamine (GlcNAc) sugars to serine or threonine residues of nuclear and cytoplasmic proteins; G) at Ser149 disrupts MDM2 binding and promotes p53 stability. Mutations abolishing _O_-GlcNAc on p53 enhances degradation. b | In quiescent cells, the oncoprotein MYC is _O_-GlcNAcylated at Thr58. Upon growth signals, the _O_-GlcNAc modification is rapidly removed, and the protein is phosphorylated at Ser62. This site is a priming site for glycogen synthase kinase 3β (GSK3β), which can then phosphorylate Thr58, leading to the rapid degradation of MYC. Numerous solid tumours have mutations at Thr58, which promotes increased MYC stability and altered gene transcription. Inhibition of GSK3β by lithium chloride (LiCl) or mutations at Ser62 increases _O_-GlcNAcylation at Thr58.

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