ETS Transcription Factor ESE1/ELF3 Orchestrates a Positive Feedback Loop That Constitutively Activates NF-κB and Drives Prostate Cancer Progression

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-07, Vol.73 (14), p.4533-4547
• Main Authors: LONGONI, Nicole, SARTI, Manuela, SESSA, Fausto, GARCIA-ESCUDERO, Ramon, THALMANN, George N, CHIORINO, Giovanna, CATAPANO, Carlo V, CARBONE, Giuseppina M, ALBINO, Domenico, CIVENNI, Gianluca, MALEK, Anastasia, ORTELLI, Erica, PINTON, Sandra, MELLO-GRAND, Maurizia, OSTANO, Paola, D'AMBROSIO, Gioacchino
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Disease Progression; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression; Gene Knockdown Techniques; Gynecology. Andrology. Obstetrics; Heterografts; Humans; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Male; Male genital diseases; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nephrology. Urinary tract diseases; NF-kappa B - genetics; NF-kappa B - metabolism; Pharmacology. Drug treatments; Prognosis; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-ets - genetics; Proto-Oncogene Proteins c-ets - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Transcriptional Activation; Transcriptome; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-4537

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.