TY - JOUR
T1 - Unveiling the association of STAT3 and HO-1 in prostate cancer
T2 - Role beyond heme degradation
AU - Elguero, Belen
AU - Gueron, Geraldine
AU - Giudice, Jimena
AU - Toscani, Martin A.
AU - de Luca, Paola
AU - Zalazar, Florencia
AU - Coluccio-Leskow, Federico
AU - Meiss, Roberto
AU - Navone, Nora
AU - de Siervi, Adriana
AU - Vazquez, Elba
N1 - Funding Information:
Address all correspondence to: Prof. Elba Vazquez, PhD, Intendente Guiraldes 2160, Ciudad Universitaria, Pabellón II, 2do Piso, 1428 Buenos Aires, Argentina. E-mail: elba@qb.fcen.uba.ar 1This work was supported by grants from the University of Buenos Aires, Argentina, UBACyT (20020100100179) and ANPCYT (PICT RAICES 2010-0431). The authors disclose no potential conflicts of interest. Received 18 August 2012; Revised 13 September 2012; Accepted 14 September 2012 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1593/neo.121358
PY - 2012/11
Y1 - 2012/11
N2 - 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.
AB - 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.
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U2 - 10.1593/neo.121358
DO - 10.1593/neo.121358
M3 - Article
C2 - 23226098
AN - SCOPUS:84869195419
SN - 1522-8002
VL - 14
SP - 1043
EP - 1056
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 11
ER -