Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Aug 12:4:99.
doi: 10.3389/fendo.2013.00099. eCollection 2013.

O-GlcNAcylation: A New Cancer Hallmark?

Yann Fardini  1 , Vanessa Dehennaut, Tony Lefebvre, Tarik Issad
Affiliations

O-GlcNAcylation: A New Cancer Hallmark?

Yann Fardini et al. Front Endocrinol (Lausanne). .

Abstract

O-linked N-acetylglucosaminylation (O-GlcNAcylation) is a reversible post-translational modification consisting in the addition of a sugar moiety to serine/threonine residues of cytosolic or nuclear proteins. Catalyzed by O-GlcNAc-transferase (OGT) and removed by O-GlcNAcase, this dynamic modification is dependent on environmental glucose concentration. O-GlcNAcylation regulates the activities of a wide panel of proteins involved in almost all aspects of cell biology. As a nutrient sensor, O-GlcNAcylation can relay the effects of excessive nutritional intake, an important cancer risk factor, on protein activities and cellular functions. Indeed, O-GlcNAcylation has been shown to play a significant role in cancer development through different mechanisms. O-GlcNAcylation and OGT levels are increased in different cancers (breast, prostate, colon…) and vary during cell cycle progression. Modulating their expression or activity can alter cancer cell proliferation and/or invasion. Interestingly, major oncogenic factors have been shown to be directly O-GlcNAcylated (p53, MYC, NFκB, β-catenin…). Furthermore, chromatin dynamics is modulated by O-GlcNAc. DNA methylation enzymes of the Tet family, involved epigenetic alterations associated with cancer, were recently found to interact with and target OGT to multi-molecular chromatin-remodeling complexes. Consistently, histones are subjected to O-GlcNAc modifications which regulate their function. Increasing number of evidences point out the central involvement of O-GlcNAcylation in tumorigenesis, justifying the attention received as a potential new approach for cancer treatment. However, comprehension of the underlying mechanism remains at its beginnings. Future challenge will be to address directly the role of O-GlcNAc-modified residues in oncogenic-related proteins to eventually propose novel strategies to alter cancer development and/or progression.

Keywords: O-GlcNAc; O-glycosylation; cancer; cell cycle; epigenetics; metastasis; post-translational modification; transcription factors.

PubMed Disclaimer

Figures

Figure 1
Figure 1
The hexosamine biosynthetic pathway and protein O-GlcNAcylation. The hexosamine biosynthetic pathway (HBP) controls O-GlcNAc glycosylation (O-GlcNAcylation) of nuclear and cytosolic proteins. This dynamic and reversible post-translational modification controls activity, localization, or stability of substrate proteins, according to the rate of glucose availability. A fraction (2–3%) of glucose entering the cell is directed to the HBP. In this pathway, fructose-6-phosphate is converted to glucosamine-6-phosphate by the glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme of the pathway. After a subset of reactions, UDP-N-acetylglucosamine (UDP-GlcNAc) is generated and used by the O-GlcNAc-transferase (OGT) as a substrate to add GlcNAc to serine or threonine residues of target proteins. O-GlcNAc moiety is removed from O-GlcNAc-modified proteins by the O-GlcNAcase (OGA). Experimentally, the level of O-GlcNAc-modified proteins in cells can be manipulated by exposing cells to high glucose concentrations or to glucosamine which enters the HBP downstream the rate-limiting GFAT-mediated reaction, as glucosamine-6-phosphate. In addition, OGA can be inhibited by pharmacological agents such as O-[2-acetamid-O-2-deoxy-D-glucopyranosylidene] amino-N-phenylcarbamate (PUGNAc) or 1,2-dideoxy-2′-propyl-alpha-d-glucopyranoso-[2,1-D]-Delta 2′-thiazoline (NButGT), resulting in an accumulation of O-GlcNAc-modified proteins in the cell.
Figure 2
Figure 2
O-GlcNAcylation and cell cycle. A quiescent cell enters the cell cycle upon mitogenic signals. Cell cycle is divided into four phases: the G1 (Gap1) phase, during which cell grows, followed by the S phase of DNA replication, then the G2 (Gap2) phase which prepares the cell for the proper division phase called M phase. Progression of the cell through the different phases is highly controlled: at the G1/S and G2/M transitions a checkpoint exists to ensure that DNA is not damaged respectively before and after its replication. The G2/M checkpoint also controls that replication is ended before division of the cell into two daughter cells genetically identical. O-GlcNAcylation levels have been found to vary all along the cell cycle suggesting that it could regulate this process. OGT and O-GlcNAcylation levels increase when quiescent cells are stimulated by mitogenic signals to enter into the cell cycle (G0/G1 transition). On the contrary, OGA activity is increased at the G1/S transition leading to a decrease in global O-GlcNAcylation levels. At the G2/M checkpoint, a burst in O-GlcNAcylation occurs. In agreement with these observations, O-GlcNAcylation has been demonstrated to be crucial for cell cycle entry and progress. Inhibition of OGT delays serum-stimulated MAPK and PI3K pathways activation and cell cycle entry whereas OGA inhibition accelerates the process. Moreover, inhibiting OGT in G2-like Xenopus laevis oocytes prevents entry into M phase. In addition, the levels of cyclin D1 and cyclin B1, two key regulators of the G1 and the M phase respectively, decrease when OGT is inhibited. Finally, O-GlcNAcylation could take part in the control of DNA replication since it modifies several histones and three proteins of the MCM (Mini Chromosome Maintenance Complex) 3, 6, and 7 that belong to the DNA pre-replication complex. As a consequence, deregulation of O-GlcNAcylation processes could contribute to perturbation in cell cycle control leading to anarchic proliferation, but also in accumulation of DNA mutations, two well established characteristics of cancer cells.
Figure 3
Figure 3
O-GlcNAcylation and oncogenic transcription factors. Several transcription factors have been described to be O-GlcNAcylated by the O-GlcNAc-transferase (OGT) among which some that are involved in tumorigenesis. The proto-oncogene MYC has been shown to be O-GlcNAcylated on Thr58. This site is normally phosphorylated by GSK3β in response to MYC phosphorylation on Ser62 resulting in MYC degradation. Proper experimental evidences demonstrating that O-GlcNAcylation promotes MYC stability and pro-oncogenic activities remain to be described. NF-κB signaling is known to be promoted by O-GlcNAcylation. First, the IKKβ kinase responsible for NF-κB activation has been shown to be to O-GlcNAcylated on Ser733. In a p53-null context, it was associated with pro-oncogenic activity in a model of colitis-associated cancer. Second, NF-κB itself is also O-GlcNAcylated at Thr322 and Thr352 in presence of high glucose concentration. In pancreatic cancer cells, Thr322 and Thr352 O-GlcNAcylation were shown to be involved in cell anchorage in vitro. In breast and prostatic cancer cells, OGT controls the expression of FOXM1, a pro-oncogenic transcriptional factor. However, FOXM1, itself, is not O-GlcNAcylated. Through an unknown substrate and mechanism, OGT prevents FOXM1 degradation and thus promotes tumor development in breast cancer and metastasis in prostate cancer. β-Catenin, involved in cell adherent junctions, is also central to the Wnt/β-catenin pathway as a transcription factor in complex notably with LEF/TCF co-factors. Once activated, β-catenin promotes tumorigenesis, especially colorectal and liver cancers. Increased O-GlcNAcylation levels of β-catenin have been observed in colon carcinoma cells. Furthermore, interaction of OGT with β-catenin is stimulated during serum-induced proliferation in HeLa cells. These observations support a positive role of O-GlcNAc-modified β-catenin in cell proliferation. The well known tumor suppressor p53 is O-GlcNAcylated at Ser149 which prevents the phosphorylation at Thr155 by the COP9 signalosome. This results in an inhibition of p53 degradation. O-GlcNAcylation of p53 promotes p53 stability and thus its tumor suppressor activity in physiological context. In case of pro-oncogenic p53 mutants, O-GlcNAc-mediated stability of p53 may favor pro-oncogenic processes. This hypothesis has not been addressed experimentally yet.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Dossus L, Kaaks R. Nutrition, metabolic factors and cancer risk. Best Pract Res Clin Endocrinol Metab (2008) 22:551–7110.1016/j.beem.2008.08.003 - DOI - PubMed
    1. Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med (2010) 61:301–1610.1146/annurev.med.080708.082713 - DOI - PubMed
    1. Simon D, Balkau B. Diabetes mellitus, hyperglycaemia and cancer. Diabetes Metab (2010) 36:182–9110.1016/j.diabet.2010.04.001 - DOI - PubMed
    1. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer (2004) 4:579–9110.1038/nrc1408 - DOI - PubMed
    1. Ashrafian H, Ahmed K, Rowland SP, Patel VM, Gooderham NJ, Holmes E, et al. Metabolic surgery and cancer: protective effects of bariatric procedures. Cancer (2010) 117:1788–9910.1002/cncr.25738 - DOI - PubMed