title: ETS transcription factor ESE1/ELF3 orchestrates a positive feedback loop that constitutively activates NF-κB and drives prostate cancer progression.
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.
authors.affiliation: Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Longoni
authors.forename: Manuela
authors.initials: M
authors.lastname: Sarti
authors.forename: Domenico
authors.initials: D
authors.lastname: Albino
authors.forename: Gianluca
authors.initials: G
authors.lastname: Civenni
authors.forename: Anastasia
authors.initials: A
authors.lastname: Malek
authors.forename: Erica
authors.initials: E
authors.lastname: Ortelli
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinton
authors.forename: Maurizia
authors.initials: M
authors.lastname: Mello-Grand
authors.forename: Paola
authors.initials: P
authors.lastname: Ostano
authors.forename: Gioacchino
authors.initials: G
authors.lastname: D'Ambrosio
authors.forename: Fausto
authors.initials: F
authors.lastname: Sessa
authors.forename: Ramon
authors.initials: R
authors.lastname: Garcia-Escudero
authors.forename: George N
authors.initials: GN
authors.lastname: Thalmann
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chiorino
authors.forename: Carlo V
authors.initials: CV
authors.lastname: Catapano
authors.forename: Giuseppina M
authors.initials: GM
authors.lastname: Carbone
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: D004268:DNA-Binding Proteins; C105529:ELF3 protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors