ETS1 induces transforming growth factor β signaling and promotes epithelial‐to‐mesenchymal transition in prostate cancer cells. Issue 1 (30th August 2018)

• Record Type: Journal Article
• Authors: Rodgers, Jamie J.; McClure, Robert; Epis, Michael R.; Cohen, Ronald J.; Leedman, Peter J.; Harvey, Jennet M.; Thomas, Marc A.; Bentel, Jacqueline M.
• Is Part Of: Journal of cellular biochemistry. Volume 120:Issue 1(2019)
• Page Start: 848
• Page End: 860
• Publication Date: 2018-08-30
• Subjects: epithelial‐to‐mesenchymal transition -- ETS factor, prostate cancer -- transforming growth factor β signaling; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.27446
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: Expression of the transcriptional regulator, E26 transformation‐specific 1 (ETS1), is elevated in human prostate cancers, and this is associated with more aggressive tumor behavior and a rapid progression to castrate‐resistant disease. Multiple ETS1 isoforms with distinct biological activities have been characterized and in 44 matched nonmalignant and malignant human prostate specimens, messenger RNAs for two ETS1 isoforms, ETS1p51 and ETS1p42, were detected, with ETS1p51 levels significantly lower in prostate tumor compared to matched nonmalignant prostate tissues. In contrast, ETS1p51 protein, the only ETS1 isoform detected, was expressed at significantly higher levels in malignant prostate. Analysis of epithelial‐to‐mesenchymal transition (EMT)–associated genes regulated following overexpression of ETS1p51 in the LNCaP prostate cancer cell line predicted promotion of transforming growth factor β (TGFβ) signaling and of EMT. ETS1p51 overexpression upregulated cellular levels of the EMT transcriptional regulators, ZEB1 and SNAIL1, resulted in reduced expression of the mesenchymal marker vimentin with concomitantly elevated levels of claudin 1, an epithelial tight junction protein, and increased prostate cancer cell migration and invasion. ETS1p51‐induced activation of the pro‐EMT TGFβ signaling pathway that was predicted in polymerase chain reaction arrays was verified by demonstration of elevated SMAD2 phosphorylation following ETS1p51 overexpression. Attenuation of ETS1p51 effects on prostate cancer cell migration and invasion by inhibition of TGFβ pathway signaling indicated that ETS1p51 effects were in part mediated by induction of TGFβ signaling. Thus, overexpression of ETS1p51, the predominant ETS1 isoform expressed in prostate tumors, promotes an EMT program in prostate cancer cells in part via activation of TGFβ signaling, potentially accounting for the poor prognosis of ETS1‐overexpressing prostate tumors. Abstract : Prostate tumors that express elevated levels of the E26 transformation‐specific 1 (ETS1) transcription factor exhibit accelerated progression to castrate‐resistant disease. In this study, we show that the ETS1p51 isoform is specifically expressed in human prostate tumors. ETS1p51 overexpression in prostate cancer cells promotes an epithelial‐to‐mesenchymal transition (EMT) program characterized by upregulated expression of the EMT transcription factors zinc finger E‐box binding homeobox 1 (ZEB1) and SNAIL1 and increased cell migration and invasion. This is in part mediated by ETS1p51‐induced transforming growth factor β (TGFβ) pathway activation, with TGFβ signaling inhibition attenuating ETS1p51‐induced effects on cell migration and invasion.