Unveiling the association of STAT3 and HO-1 in prostate cancer: Role beyond heme degradation
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 pr...
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todo:paper_15228002_v14_n11_p1043_Elguero2023-10-03T16:20:49Z Unveiling the association of STAT3 and HO-1 in prostate cancer: Role beyond heme degradation Elguero, B. Gueron, G. Giudice, J. Toscani, M.A. de Luca, P. Zalazar, F. Coluccio-Leskow, F. Meiss, R. Navone, N. de Siervi, A. Vazquez, E. androgen receptor cyclin D1 heme oxygenase 1 hemin interleukin 6 messenger RNA prostate specific antigen protein bcl xl STAT3 protein survivin testosterone animal experiment animal model animal tissue article cellular distribution chromatin immunoprecipitation confocal laser microscopy confocal microscopy controlled study gene overexpression human human cell immunocytochemistry immunofluorescence test immunohistochemistry immunoreactivity molecular interaction mouse nonhuman priority journal promoter region prostate cancer protein expression protein localization protein synthesis regulation real time polymerase chain reaction reverse transcription polymerase chain reaction signal transduction Western blotting 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. © 2012 Neoplasia Press, Inc. All rights reserved. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_15228002_v14_n11_p1043_Elguero |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
androgen receptor cyclin D1 heme oxygenase 1 hemin interleukin 6 messenger RNA prostate specific antigen protein bcl xl STAT3 protein survivin testosterone animal experiment animal model animal tissue article cellular distribution chromatin immunoprecipitation confocal laser microscopy confocal microscopy controlled study gene overexpression human human cell immunocytochemistry immunofluorescence test immunohistochemistry immunoreactivity molecular interaction mouse nonhuman priority journal promoter region prostate cancer protein expression protein localization protein synthesis regulation real time polymerase chain reaction reverse transcription polymerase chain reaction signal transduction Western blotting |
| spellingShingle |
androgen receptor cyclin D1 heme oxygenase 1 hemin interleukin 6 messenger RNA prostate specific antigen protein bcl xl STAT3 protein survivin testosterone animal experiment animal model animal tissue article cellular distribution chromatin immunoprecipitation confocal laser microscopy confocal microscopy controlled study gene overexpression human human cell immunocytochemistry immunofluorescence test immunohistochemistry immunoreactivity molecular interaction mouse nonhuman priority journal promoter region prostate cancer protein expression protein localization protein synthesis regulation real time polymerase chain reaction reverse transcription polymerase chain reaction signal transduction Western blotting Elguero, B. Gueron, G. Giudice, J. Toscani, M.A. de Luca, P. Zalazar, F. Coluccio-Leskow, F. Meiss, R. Navone, N. de Siervi, A. Vazquez, E. Unveiling the association of STAT3 and HO-1 in prostate cancer: Role beyond heme degradation |
| topic_facet |
androgen receptor cyclin D1 heme oxygenase 1 hemin interleukin 6 messenger RNA prostate specific antigen protein bcl xl STAT3 protein survivin testosterone animal experiment animal model animal tissue article cellular distribution chromatin immunoprecipitation confocal laser microscopy confocal microscopy controlled study gene overexpression human human cell immunocytochemistry immunofluorescence test immunohistochemistry immunoreactivity molecular interaction mouse nonhuman priority journal promoter region prostate cancer protein expression protein localization protein synthesis regulation real time polymerase chain reaction reverse transcription polymerase chain reaction signal transduction Western blotting |
| description |
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. © 2012 Neoplasia Press, Inc. All rights reserved. |
| format |
JOUR |
| author |
Elguero, B. Gueron, G. Giudice, J. Toscani, M.A. de Luca, P. Zalazar, F. Coluccio-Leskow, F. Meiss, R. Navone, N. de Siervi, A. Vazquez, E. |
| author_facet |
Elguero, B. Gueron, G. Giudice, J. Toscani, M.A. de Luca, P. Zalazar, F. Coluccio-Leskow, F. Meiss, R. Navone, N. de Siervi, A. Vazquez, E. |
| author_sort |
Elguero, B. |
| title |
Unveiling the association of STAT3 and HO-1 in prostate cancer: Role beyond heme degradation |
| title_short |
Unveiling the association of STAT3 and HO-1 in prostate cancer: Role beyond heme degradation |
| title_full |
Unveiling the association of STAT3 and HO-1 in prostate cancer: Role beyond heme degradation |
| title_fullStr |
Unveiling the association of STAT3 and HO-1 in prostate cancer: Role beyond heme degradation |
| title_full_unstemmed |
Unveiling the association of STAT3 and HO-1 in prostate cancer: Role beyond heme degradation |
| title_sort |
unveiling the association of stat3 and ho-1 in prostate cancer: role beyond heme degradation |
| url |
http://hdl.handle.net/20.500.12110/paper_15228002_v14_n11_p1043_Elguero |
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