Abstract A023: Regulation of ERG function in prostate cells by phosphorylation and interaction with Ewing’s sarcoma breakpoint protein EWS

Abstract

More than one-half of prostate tumors have a chromosomal rearrangement that results in the overexpression of an oncogenic ETS family transcription factor. The most common fusion, TMPRSS2/ERG, results in expression of ERG, a protein that is not normally expressed in prostate epithelia. When ERG is expressed in prostate cells it is thought to bind to enhancer elements and regulate gene expression by recruiting transcriptional coactivators and/or corepressors. We have recently shown that the EWS protein acts as a coactivator for ERG in prostate cells and this interaction is required for ERG-mediated xenograft tumor growth. Interestingly, the EWS interaction may be the key requirement that separates oncogenic from nononcogenic ETS factors, as EWS only interacts with four ETS family members involved in prostate cancer gene rearrangements (ERG, ETV1, ETV4, and ETV5), but not with other ETS family members. This ETS/EWS interaction also indicates a common molecular mechanism involved in prostate cancer and Ewing’s sarcoma, a cancer caused by gene fusions that express chimeric EWS/ETS proteins. ERG also interacts with corepressors such as EZH2, a subunit of PRC2. We have recently found that the interaction between ERG and EZH2/PRC2 is regulated by a series of phosphorylation events on ERG. The MAP kinase ERK can bind a high-affinity docking sequence in ERG, resulting in phosphorylation of a nearby serine, S215. This phosphorylation event leads to a conformational change in ERG that allows ERK to phosphorylate a second serine, S96. S96 phosphorylation then disrupts the interaction between ERG and EZH2/PRC2, allowing ERG to activate gene expression. Together, the interaction of ERG with EWS and the regulation of ERG function by ERK-mediated phosphorylation, represent molecular mechanisms that could serve as targets for therapeutic intervention in ERG-positive prostate cancer. Citation Format: Vivekananda Kedage, Taylor R. Nicholas, Brady G. Strittmatter, Nagarathinam Selvaraj, Justin A. Budka, Travis J. Jerde, Peter C. Hollenhorst. Regulation of ERG function in prostate cells by phosphorylation and interaction with Ewing’s sarcoma breakpoint protein EWS [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A023.