ETS transcription factor ESE1/ELF3 orchestrates a positive feedback loop that constitutively activates NF-κB and drives prostate cancer progression

N Longoni, M Sarti, D Albino, G Civenni, A Malek… - Cancer research, 2013 - AACR
N Longoni, M Sarti, D Albino, G Civenni, A Malek, E Ortelli, S Pinton, M Mello-Grand…
Cancer research, 2013AACR
Chromosomal translocations leading to deregulated expression of ETS transcription factors
are frequent in prostate tumors. Here, we report a novel mechanism leading to oncogenic
activation of the ETS factor ESE1/ELF3 in prostate tumors. ESE1/ELF3 was overexpressed
in human primary and metastatic tumors. It mediated transforming phenotypes in vitro and in
vivo and induced an inflammatory transcriptome with changes in relevant oncogenic
pathways. ESE1/ELF3 was induced by interleukin (IL)-1β through NF-κB and was a crucial …
Abstract
Chromosomal translocations leading to deregulated expression of ETS transcription factors are frequent in prostate tumors. Here, we report a novel mechanism leading to oncogenic activation of the ETS factor ESE1/ELF3 in prostate tumors. ESE1/ELF3 was overexpressed in human primary and metastatic tumors. It mediated transforming phenotypes in vitro and in vivo and induced an inflammatory transcriptome with changes in relevant oncogenic pathways. ESE1/ELF3 was induced by interleukin (IL)-1β through NF-κB and was a crucial mediator of the phenotypic and transcriptional changes induced by IL-1β in prostate cancer cells. This linkage was mediated by interaction of ESE1/ELF3 with the NF-κB subunits p65 and p50, acting by enhancing their nuclear translocation and transcriptional activity and by inducing p50 transcription. Supporting these findings, gene expression profiling revealed an enrichment of NF-κB effector functions in prostate cancer cells or tumors expressing high levels of ESE1/ELF3. We observed concordant upregulation of ESE1/ELF3 and NF-κB in human prostate tumors that was associated with adverse prognosis. Collectively, our results define an important new mechanistic link between inflammatory signaling and the progression of prostate cancer. Cancer Res; 73(14); 4533–47. ©2013 AACR.
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