Abstract 4007: Defining the role of ERG-mediated repression of HPGD in prostate tumorigenesis

Abstract

Abstract Activation of the ETS Related Gene (ERG) was originally identified in subsets of Ewing sarcomas, myeloid leukemias and, recently, in the majority of prostate cancers (CaP). Emerging studies in experimental models underscore functions of ERG in prostate tumorigenesis. However, biological functions of ERG in CaP remains to be better understood. Evaluation of ERG downstream targets identified 15-hydroxyprostaglandin dehydrogenase gene (HPGD) in response to ERG knockdown. Several recent studies have indicated that HPGD, the main catabolizing enzyme of prostaglandins and lipoxins and a tumor suppressor, is down-regulated in a majority of lung, colon, breast, and bladder cancers. However, the regulation of HPGD within the biological context of ERG expressing prostate tumors remains to be defined. The objective of this study was to evaluate the effects of ERG on the prostaglandin signaling pathway in prostate cancer. Correlation between HPGD and ERG expression was evaluated at the mRNA and protein levels in prostate cancer specimens and cell lines by Western blot, QRT-PCR, and immunofluorescence assays. Small interference RNA against human ERG and HPGD were used to knock-down their respective expressions. Functional consequences of ERG and HPGD knockdown in VCaP cells harboring TMPRSS2-ERG fusions were assessed by ChIP and BrdU cell proliferation assays. The experiments showed that loss of ERG expression leads to a robust overexpression of HPGD in prostate cancer cells. Furthermore, we observed altered PGE2 production, decreased expression of prostaglandin E2 receptor 4 (EP4), and inhibition of prostaglandin E2 induced cell growth. Chromatin immunoprecipitation experiments revealed direct binding of ERG protein to the HPGD core promoter. Comparison of HPGD expression in TMPRSS2-ERG positive and negative prostate tumors indicated a trend towards decreased HPGD expression. In conclusion ERG activation, as a consequence of TMPRSS2-ERG fusions, may influence the components of the prostaglandin signaling pathway in prostate tumorigenesis disrupting the tumor suppressor functions of HPGD. These findings suggests for a new biological role of ERG in CaP that may be further evaluated as a target for prevention, as well as early therapeutic intervention in CaP. 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 4007. doi:10.1158/1538-7445.AM2011-4007