GSE159471
Methylation-induced conformational switch enables ERG oncogenic activation and  prostate cancer progression
The TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate  cancer but its role in disease progression is still debated. In this study, we uncovered a novel  molecular mechanism promoting progression in ERG-fusion positive prostate cancer. We show  that ERG is methylated by Enhancer of zest homolog 2 (EZH2) at a specific lysine residue    (K362) located within the internal auto-inhibitory domain. Mechanistically, K362 mono-  methylation prevents intra-domain interactions, favors DNA binding and promotes ERG    transcriptional and oncogenic activity in cellular and mouse models. Consistently with the  involvement in ERG oncogenesis, we found that K362 methylation was associated with disease  progression in ERG transgenic mouse models and was enhanced by PTEN deficiency and AKT  activation, which promoted EZH2 substrate switching from histone H3K27 to ERG.  Conversely, EZH2 inhibition blocked ERG methylation along with ERG-induced  transcriptional and phenotypic reprogramming in cell cultures and ERG/PTEN mice. We found  that ERG and EZH2 co-occupy several genomic regions forming prevalently co-activating  complexes. The network of ERG/EZH2 co-regulated target genes was enriched of functionally  aggressive features and was associated preferentially with concomitant ERG gain and PTEN  loss, castration-resistance and adverse clinical outcome in prostate cancer patients. Collectively,  these findings identify ERG methylation as a novel post-translational modification sustaining  disease progression in ERG-positive prostate cancers. Our data also provide an attractive  rationale for developing molecularly targeted therapeutics to antagonize ERG oncogenic  activity. Overall design: Examination of mERG bindings in TMPRSS2/ERG positive VCaP cells.