Title : O-GlcNAcylation regulates
EZH2 protein stability and function
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 methyl transferase enhancer of zeste homolog 2 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 H3 K27 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