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PMID:24474760

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Citation

Chu, CS, Lo, PW, Yeh, YH, Hsu, PH, Peng, SH, Teng, YC, Kang, ML, Wong, CH and Juan, LJ (2014) O-GlcNAcylation regulates EZH2 protein stability and function. Proc. Natl. Acad. Sci. U.S.A. 111:1355-60

Abstract

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 O-GlcNAcylation, 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.

Links

PubMed PMC3910655 Online version:10.1073/pnas.1323226111

Keywords

Acetylglucosamine/metabolism; DNA Methylation; Down-Regulation; Gene Knockdown Techniques; Genes, Tumor Suppressor; Humans; N-Acetylglucosaminyltransferases/genetics; N-Acetylglucosaminyltransferases/metabolism; Polycomb Repressive Complex 2/metabolism; Protein Stability

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:OGT1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15910

F

Seeded From UniProt

complete

HUMAN:EZH2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O15294

F

Seeded From UniProt

complete

HUMAN:EZH2

involved_in

GO:0070734: histone H3-K27 methylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EZH2

part_of

GO:0035098: ESC/E(Z) complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:EZH2

enables

GO:0046976: histone methyltransferase activity (H3-K27 specific)

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:OGT1

enables

GO:0016262: protein N-acetylglucosaminyltransferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:OGT1

involved_in

GO:0006493: protein O-linked glycosylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:OGT1

involved_in

GO:0061087: positive regulation of histone H3-K27 methylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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