Tumor and Stem Cell Biology ETS Transcription Factor ESE1/ELF3 Orchestrates a Positive Feedback Loop That Constitutively Activates NF-kB and Drives Prostate Cancer Progression

Chromosomal translocations leading to deregulated expression of ETS transcription factors are frequent in prostate tumors. Here, we report a novelmechanism 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)-1b through NF-kB and was a crucial mediator of the phenotypic and transcriptional changes induced by IL-1b in prostate cancer cells. This linkage was mediated by interaction of ESE1/ELF3 with the NF-kB 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-kB effector functions in prostate cancer cells or tumors expressing high levels of ESE1/ELF3. We observed concordant upregulation of ESE1/ELF3 and NF-kB 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);