ERG Activates the YAP1 Transcriptional Program and Induces the Development of Age-Related Prostate Tumors

The significance of ERG in human prostate cancer is unclear because mouse prostate is resistant to ERG-mediated transformation. We determined that ERG activates the transcriptional program regulated by YAP1 of the Hippo signaling pathway and found that prostate-specific activation of either ERG or YAP1 in mice induces similar transcriptional changes and results in age-related prostate tumors. ERG binds to chromatin regions occupied by TEAD/YAP1 and transactivates Hippo target genes. In addition, in human luminal-type prostate cancer cells, ERG binds to the promoter of YAP1 and is necessary for YAP1 expression. These results provide direct genetic evidence of a causal role for ERG in prostate cancer and reveal a connection between ERG and the Hippo signaling pathway. •Upregulation of ERG is sufficient to cause age-dependent prostate tumors in mice•ERG transcriptional output is similar to the output of YAP1 of the Hippo pathway•ERG is necessary for YAP1 expression in luminal-type human prostate cancer cells•Activation of YAP1 is sufficient to cause age-dependent prostate tumors in mice Nguyen et al. show that ERG activates YAP1-regulated transcriptional output and that activation of ERG or YAP1 in mouse prostate induces similar transcriptional changes and age-related prostate tumors. Moreover, pharmacological inhibition of YAP1 suppresses growth of ERG-positive human prostate tumor xenografts.