Abstract 2159: Molecular characterization of ERG mediated CXCR4 transcriptional regulation

Abstract

Abstract CXCR4 is a chemokine receptor, which has been shown to be expressed in several types of tumor cells, and mediate invasion and metastasis. CXCR4 expression is transcriptionally regulated in cancer cells and is associated with aggressive phenotypes of prostate cancer. Previously, we and others have shown that ERG transcription factor regulates CXCR4 expression in prostate cancer cells. In prostate cancer patients ERG is expressed via chromosomal alterations resulting in fusion of androgen responsive TMPRSS2 promoter with the coding sequence of ERG transcription factor and systemic androgens regulate ERG expression. We further show that in TMPRSS2-ERG fusion positive prostate cancer cells androgens regulate CXCR4 expression via activating ERG transcription factor expression. The CXCR4 promoter contains several putative ERG/Ets transcription factor binding sites. We hypothesize that ERG binds to selective ERG/Ets binding sites in the CXCR4 promoter and activates CXCR4 expression. Using electrophoretic mobility shift assay experiments with each of the individual ERG/Ets binding sites with VCaP cell nuclear extracts and in vitro translated ERG protein, sequential ERG/Ets binding site deletions in CXCR4 promoter reporters, chromatin immunoprecipitation experiments with anti-ERG antibodies in TMPRSS2-ERG positive VCaP cells, and chemoinvasion studies with VCaP cells we show that: (a) ERG expressed in VCaP cells selectively interacts with specific ERG/Ets bindings sites in the CXCR4 promoter; (b) several Ets factor family members are expressed in VCaP cells; (c) in vitro translated ERG binding with ERG/Ets elements in CXCR4 promoter further confirms that selective ERG/Ets sites in CXCR4 promoter are active in binding with ERG; (d) ERG binds with CXCR4 gene promoter in VCaP cells; (e) androgens regulate CXCR4 expression in TMPRSS2-ERG fusion positive cells; and (f) androgen induced CXCR4 is active in chemoinvasion of prostate cancer cells. These data suggest that androgens regulate CXCR4 expression via ERG transcription factor expression and ERG factor may regulate CXCR4 expression by binding to the specific ERG/Ets responsive elements and activating CXCR4 transcription. These findings may provide a link between TMPRSS2-ERG translocations and enhanced metastasis of tumor cells via CXCR4 function in PC cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2159. doi:10.1158/1538-7445.AM2011-2159