ETS transcription factor ERG cooperates with histone demethylase KDM4A

ERG (ETS-related gene) is a member of the ETS (erythroblast transformation-specific) family of transcription factors. Overexpression of the ERG transcription factor is observed in half of all prostate tumors and is an underlying cause of this disease. However, the mechanisms involved in the functions of ERG are still not fully understood. In the present study, we showed that ERG can directly bind to KDM4A (also known as JMJD2A), a histone demethylase that particularly demethylates lysine 9 on histone H3. ERG and KDM4A cooperated in upregulating the promoter of Yes-associated protein 1 (YAP1), a downstream effector in the Hippo signaling pathway and crucial growth regulator. Multiple ERG binding sites within the human YAP1 gene promoter were identified and their impact on transcription was determined through mutational analysis. Furthermore, we found that ERG expression reduced histone H3 lysine 9 trimethylation at the YAP1 gene promoter, consistent with its epigenetic regulation through the ERG interaction partner, KDM4A. Finally, downregulation of YAP1 phenocopied the growth-retarding effect of ERG or KDM4A depletion in human VCaP prostate cancer cells. Collectively, these results elucidated a novel mechanism - ERG promotes prostate tumorigenesis together with KDM4A through the upregulation of YAP1. A corollary is that KDM4A as well as YAP1 inhibitors may prove beneficial for the therapy of ERG-overexpressing prostate tumors.