title: Unveiling the association of STAT3 and HO-1 in prostate cancer: role beyond heme degradation.
abstract: Activation of the androgen receptor (AR) is a key step in the development of prostate cancer (PCa). Several mechanisms have been identified in AR activation, among them signal transducer and activator of transcription 3 (STAT3) signaling. Disruption of STAT3 activity has been associated to cancer progression. Recent studies suggest that heme oxygenase 1 (HO-1) may play a key role in PCa that may be independent of its catalytic function. We sought to explore whether HO-1 operates on AR transcriptional activity through the STAT3 axis. Our results display that HO-1 induction in PCa cells represses AR activation by decreasing the prostate-specific antigen (PSA) promoter activity and mRNA levels. Strikingly, this is the first report to show by chromatin immunoprecipitation analysis that HO-1 associates to gene promoters, revealing a novel function for HO-1 in the nucleus. Furthermore, HO-1 and STAT3 directly interact as determined by co-immunoprecipitation studies. Forced expression of HO-1 increases STAT3 cytoplasmic retention. When PCa cells were transfected with a constitutively active STAT3 mutant, PSA and STAT3 downstream target genes were abrogated under hemin treatment. Additionally, a significant decrease in pSTAT3 protein levels was detected in the nuclear fraction of these cells. Confocal microscopy images exhibit a decreased rate of AR/STAT3 nuclear co-localization under hemin treatment. In vivo studies confirmed that STAT3 nuclear delimitation was significantly decreased in PC3 tumors overexpressing HO-1 grown as xenografts in nude mice. These results provide a novel function for HO-1 down-modulating AR transcriptional activity in PCa, interfering with STAT3 signaling, evidencing its role beyond heme degradation.
authors.affiliation: Department of Biological Chemistry, School of Sciences, University of Buenos Aires, Ciudad Universitaria, Pabellón II, 2do Piso, Buenos Aires, Argentina, IQUIBICEN-CONICET.
authors.forename: Belen
authors.initials: B
authors.lastname: Elguero
authors.forename: Geraldine
authors.initials: G
authors.lastname: Gueron
authors.forename: Jimena
authors.initials: J
authors.lastname: Giudice
authors.forename: Martin A
authors.initials: MA
authors.lastname: Toscani
authors.forename: Paola
authors.initials: P
authors.lastname: De Luca
authors.forename: Florencia
authors.initials: F
authors.lastname: Zalazar
authors.forename: Federico
authors.initials: F
authors.lastname: Coluccio-Leskow
authors.forename: Roberto
authors.initials: R
authors.lastname: Meiss
authors.forename: Nora
authors.initials: N
authors.lastname: Navone
authors.forename: Adriana
authors.initials: A
authors.lastname: De Siervi
authors.forename: Elba
authors.initials: E
authors.lastname: Vazquez
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D011944:Receptors, Androgen / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D011944:Receptors, Androgen; D050796:STAT3 Transcription Factor; D006418:Heme; D051547:Heme Oxygenase-1; D017430:Prostate-Specific Antigen; D020780:Matrix Metalloproteinase 9