ERG promotes the methylation reprogramming in prostate cancer onset


Session type:


Maria Giovanna de Marino1
1University of Insubria



ETS-related gene (ERG) is one of the E-26 transformation-specific family of transcription factors. Tomlins et al. demonstrated that 50% of PCa is characterized by the formation of the TMPRSS2 androgen-dependent promoter and ERG gene fusion that promotes ERG overexpression and thus contributes to an androgen-independence development.


The ERG overexpression phenotype was studied using a model based on a normal immortalized human prostate epithelial cell line, RWPE-1, engineered to allow the inducible expression of ERG by doxycycline treatment. Induced migration was assessed by the wound healing assay, while transcriptional and translational levels were defined using qPCR and Western Blotting.


ERG overexpression in normal epithelial cell line promotes a time-dependent migration. This early gain of function aligns with what we firstly confirmed, in fact, ERG overexpression assesses an initial EMT phenotype switch, promoting the upregulation of mesenchymal markers and factors such as vimentin, CDH2, and ZEB1, while on the other hand a slight reduction of CDH1 and Slug expression. Interestingly, our analyses showed that ERG upregulation also affects DNA methyltransferases expression. The maintenance and de novo methyltransferases (DNMT1 and DNMT3B, respectively) decrease both at a transcriptional and translational level, while, surprisingly, DNMT3A expression levels increase after ERG induction. In this scenario, we hypothesized that ERG overexpression promotes a global DNA methylation reprogramming to support prostate cancer progression. Besides, as we have previously demonstrated (Pistore et al., 2017), DNMT3A is able to bind the CDH1 promoter and thus contribute to the mesenchymal phenotype that we observed.


ERG overexpression contributes to PCa progression promoting an EMT acquisition. This process could be supported by a switch in DNMTs expression that allows DNMT3A to reprogram DNA methylation levels and to support mesenchymal phenotype. To deepen our hypothesis, we will carry out the silencing of DNMT3A before and after ERG induction to intercept DE and DM genes.