O-GlcNAcylation regulates EZH2 protein stability and function.

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