O-GlcNAcylation: A New Cancer Hallmark?

Fardini, Yann; Dehennaut, Vanessa; Lefebvre, Tony; Issad, Tarik

doi:10.3389/fendo.2013.00099

Cited by 217 publications

(223 citation statements)

References 127 publications

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“…Because overexpression of OGT and EZH2 has been implicated in breast tumorigenesis (43,44) and EZH2 has been known to repress specific tumor suppressor gene expression in breast cancer cells (45), microarray analysis was carried out using the breast cancer cell line MCF7 treated with scramble siRNA, siOGT, or siEZH2 (Fig. S5A).…”

Section: Ogt-ezh2 Axis Suppresses Specific Tumor Suppressor Gene Exprmentioning

confidence: 99%

O-GlcNAcylation regulates EZH2 protein stability and function

Chu

Yeh

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

196

204

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O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) is the only known enzyme that catalyzes the O-GlcNAcylation of proteins at the Ser or Thr side chain hydroxyl group. OGT participates in transcriptional and epigenetic regulation, and dysregulation of OGT has been implicated in diseases such as cancer. However, the underlying mechanism is largely unknown. Here we show that OGT is required for the trimethylation of histone 3 at K27 to form the product H3K27me3, a process catalyzed by the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in the polycomb repressive complex 2 (PRC2). H3K27me3 is one of the most important histone modifications to mark the transcriptionally silenced chromatin. We found that the level of H3K27me3, but not other H3 methylation products, was greatly reduced upon OGT depletion. OGT knockdown specifically down-regulated the protein stability of EZH2, without altering the levels of H3K27 demethylases UTX and JMJD3, and disrupted the integrity of the PRC2 complex. Furthermore, the interaction of OGT and EZH2/PRC2 was detected by coimmunoprecipitation and cosedimentation experiments. Importantly, we identified that serine 75 is the site for EZH2 OGlcNAcylation, and the EZH2 mutant S75A exhibited reduction in stability. Finally, microarray and ChIP analysis have characterized a specific subset of potential tumor suppressor genes subject to repression via the OGT-EZH2 axis. Together these results indicate that OGT-mediated O-GlcNAcylation at S75 stabilizes EZH2 and hence facilitates the formation of H3K27me3. The study not only uncovers a functional posttranslational modification of EZH2 but also reveals a unique epigenetic role of OGT in regulating histone methylation.

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Section: Ogt-ezh2 Axis Suppresses Specific Tumor Suppressor Gene Exprmentioning

confidence: 99%

O-GlcNAcylation regulates EZH2 protein stability and function

Chu

Yeh

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

196

204

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“…UDP-GlcNAc, situated at the nexus of the glucose, lipid, nucleotide and amino acid biosynthesis pathways, is believed to be a sensor for cellular metabolites. Moreover, diseases with impaired metabolism such as neurodegenerative disease, diabetes, cardiovascular disease and cancer often exhibit altered levels of cellular O-GlcNAcylation (reviewed in [12,21,22,[62][63][64][65]). …”

Section: Carm1 O-glcnacylation May Be a Sensor Of Cellular Stress Andmentioning

confidence: 99%

O-GlcNAcylation of co-activator-associated arginine methyltransferase 1 regulates its protein substrate specificity

Charoensuksai

Kühn

Wang

et al. 2015

Biochemical Journal

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Co-activator-associated arginine methyltransferase 1 (CARM1) asymmetrically di-methylates proteins on arginine residues. CARM1 was previously known to be modified through O-linked-β-N-acetylglucosaminidation (O-GlcNAcylation). However, the site(s) of O-GlcNAcylation were not mapped and the effects of O-GlcNAcylation on biological functions of CARM1 were undetermined. In the present study, we describe the comprehensive mapping of CARM1 post-translational modification (PTM) using top-down MS. We found that all detectable recombinant CARM1 expressed in human embryonic kidney (HEK293T) cells is automethylated as we previously reported and that about 50% of this automethylated CARM1 contains a single O-linked-β-N-acetylglucosamine (O-GlcNAc) moiety [31]. The O-GlcNAc moiety was mapped by MS to four possible sites (Ser595, Ser598, Thr601 and Thr603) in the C-terminus of CARM1. Mutation of all four sites [CARM1 quadruple mutant (CARM1QM)] markedly decreased O-GlcNAcylation, but did not affect protein stability, dimerization or cellular localization of CARM1. Moreover, CARM1QM elicits similar co-activator activity as CARM1 wild-type (CARM1WT) on a few transcription factors known to be activated by CARM1. However, O-GlcNAc-depleted CARM1 generated by wheat germ agglutinin (WGA) enrichment, O-GlcNAcase (OGA) treatment and mutation of putative O-GlcNAcylation sites displays different substrate specificity from that of CARM1WT. Our findings suggest that O-GlcNAcylation of CARM1 at its C-terminus is an important determinant for CARM1 substrate specificity.

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“…cancers (16,19,20), but neither has been examined previously in the context of HPV oncogene expression or cervical neoplasms. In this work, we asked whether O-GlcNAc might play a role in HPVinduced transformation and carcinogenesis.…”

mentioning

confidence: 99%

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

Zeng

Zhao

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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High-risk human papillomaviruses (HPVs) are causative agents of anogenital cancers and a fraction of head and neck cancers. The mechanisms involved in the progression of HPV neoplasias to cancers remain largely unknown. Here, we report that O-linked GlcNAcylation (O-GlcNAc) and O-GlcNAc transferase (OGT) were markedly increased in HPV-caused cervical neoplasms relative to normal cervix, whereas O-GlcNAcase (OGA) levels were not altered. Transduction of HPV16 oncogene E6 or E6/E7 into mouse embryonic fibroblasts (MEFs) up-regulated OGT mRNA and protein, elevated the level of O-GlcNAc, and promoted cell proliferation while reducing cellular senescence. Two HR HPV genes, E6 and E7, are potent oncogenes based on their immortalizing and transforming activities in cell culture systems and their capacities to induce tumors in animal models. The HR HPV E7 oncoprotein binds to more than 20 cellular targets and interferes with multiple cellular processes, leading to deregulated cell cycle, centrosome amplification, DNA damage, anoikis resistance, anchorage-independent cell growth and malignant transformation as well as immune surveillance evasion.

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O-GlcNAcylation: A New Cancer Hallmark?

Cited by 217 publications

References 127 publications

O-GlcNAcylation regulates EZH2 protein stability and function

O-GlcNAcylation regulates EZH2 protein stability and function

O-GlcNAcylation of co-activator-associated arginine methyltransferase 1 regulates its protein substrate specificity

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

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