Abstract
Abstract Background: The transcription factor ETS1 is overexpressed in up to 70% of prostate tumors. Three ETS1 isoforms which arise due to alternative splicing have been reported, ETS1p51, ETS1p42 and ETS1p27, each with distinct transcriptional activator or repressor functions. Elevated ETS1 levels in prostate tumors are correlated with more rapid progression to castrate-resistant disease and a poor prognosis, while ETS1 overexpression in vitro is correlated with increased migration and invasion of prostate cancer cells. Aim: To characterise ETS1 isoform expression in prostate tumors and to determine the effects of ETS1 overexpression on the regulation of epithelial-to-mesenchymal transition (EMT). Methods: ETS1 isoform expression was characterised in 45 malignant prostate and adjacent non-malignant prostatic tissues using isoform-specific RT-qPCR and western blotting. Expression of genes encoding regulators of EMT was screened using a Human EMT PCR array (SABiosciences) in the human prostate cancer cell line, LNCaP that had been transiently transfected to overexpress ETS1p51. RT-qPCR and western blotting were used to confirm the ETS1-induced levels of differentially expressed genes/proteins and western blotting for phospho-SMAD2 (pSMAD2)/total SMAD2 (tSMAD2) was used to investigate activation of TGF-β signalling. Results: ETS1p51 was the predominant ETS1 isoform expressed in both the normal prostate and prostate tumors, with significantly decreased mRNA (p<0.001), but significantly elevated (p<0.05) protein levels in the majority of malignant tissues. ETS1p51 overexpression increased (>1.5 fold) levels of pro-EMT regulators including members of the WNT (WNT5B, β-catenin) and TGF-β (TGF-β1/2/3) signalling pathways. Phosphorylation of the TGF-β signalling intermediate, SMAD2 was increased and mRNA/protein levels of the EMT transcriptional regulators, TWIST1, SNAIL1, SLUG and ZEB1 were also elevated. In ETS1p51 overexpressing cells, expression of the mesenchymal marker vimentin was increased, while expression of the epithelial tight-junction molecule, Claudin-1 was decreased. Together with increased expression of effectors of migration and invasion (e.g. SPARC, MMP2/9), the findings indicate induction of an EMT programme. Conclusions: Levels of ETS1p51, the predominant ETS1 isoform expressed in the prostate are upregulated by post-transcriptional mechanisms in prostate tumors. Increased ETS1p51 expression promotes TGF-β signalling and EMT, processes that are likely to contribute to the accelerated disease progression and poorer outcomes associated with ETS1 overexpressing prostate tumors. Citation Format: Jamie J. Rodgers, Michael Epis, Ronald Cohen, Peter Leedman, Jennet Harvey, Marc Thomas, Jacqueline Bentel. ETS1 regulates epithelial-to-mesenchymal transition (EMT) in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1124. doi:10.1158/1538-7445.AM2014-1124
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