Abstract B25: The ETS transcription factor ESE1 promotes activation of the NFKB pathway in prostate tumors
Authors: Longoni Nicole , Mello-Grand Maurizia , Sarti Manuela , Pinton Sandra , Dallavalle Cecilia , Chiorino Giovanna , Catapano Carlo V. , Carbone Giuseppina M. 
Published: May 2013

Abstract
ETS transcription factors are important elements in the pathogenesis of prostate cancer. Here, we report that the ETS factor ESE1, which is expressed in normal prostate epithelial cells, is frequently upregulated in prostate tumors and functionally linked to activation of the NFkB pathway and inflammation. Immunohistochemistry and QRT-PCR in normal prostate and primary prostate tumor samples showed increased expression of ESE1 in about 35% of tumors. Over-expression of ESE1 was observed both in the presence and absence of ERG over-expression, indicating that activation of ESE1 could have an independent role in a subset of prostate tumors. Furthermore, elevated levels of ESE1 were significantly associated with higher rates of biochemical relapses in patients with primary tumors treated with radical prostatectomy (Log Rank (Mantel-Cox)=0.018). Overexpression of ESE1 in prostate cancer cells, like LNCaP and 22RV1, promoted a more aggressive phenotype with increased growth in soft-agar, resistance to anoikis and cell migration. When injected in nude mice, ESE1 over-expressing prostate cancer cells exhibited greater ability to form lung metastasis compared to control cells. ESE1 affected transcription of many genes and ChIP showed binding of ESE1 to ETS binding sites in the promoter of key genes involved in cell adhesion, metastasis and inflammation. Relevantly, we observed that mRNA and protein level of the NFkB subunit NFKB1 (p50) was increased in stable ESE1 expressing cells. Analysis of NFKB1 promoter revealed the presence of a previously unknown ETS binding site and ChIP demonstrated binding of ESE1 to this site, consistent with transcriptional activation of the gene by ESE1. Immunofluorescence microscopy showed a marked intranuclear localization of the NFkB p50/p65 complex, indicating that ESE1 promoted also NFkB activation. Consistently, the activity of the NFkB-responsive luciferase reporter was increased in ESE1 expressing cells compared to control cells. Furthermore, we found that the pro-inflammatory cytokine IL-1beta increased ESE1 mRNA and protein level in LNCaP cells while promoting intranuclear localization of the NFkB complex. This was associated with the induction of anoikis resistance and cell migration. All these effects were rescued by siRNA mediated knockdown of ESE1 indicating that ESE1 had a key role in mediating the effects of IL-1beta in these cells. We propose that the production of pro-inflammatory cytokines like IL-1beta within the tumor microenvironment results in the upregulation of ESE1 and establishment of a feed-forward loop leading to the constitutive activation of the NFkB linked to the ability of ESE1 to induce p50 transcription and NFkB nuclear translocation. These data show an important oncogenic role of ESE1 in prostate tumors and reveal a previously unidentified link between this ETS factor and the NFkB pathway.
Citation Format: Nicole Longoni, Maurizia Mello-Grand, Manuela Sarti, Sandra Pinton, Cecilia Dallavalle, Giovanna Chiorino, Carlo V. Catapano, Giuseppina M. Carbone. The ETS transcription factor ESE1 promotes activation of the NFKB pathway in prostate tumors [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B25.