Association of HO-1 and BRCA1 is critical for the maintenance of cellular homeostasis in prostate cancer
Prostate cancer is the second leading cause of cancer-related death in men worldwide. Many factors that participate in the development of prostate cancer promote imbalance in the redox state of the cell. Accumulation of reactive oxygen species causes injury to cell structures, ultimately leading to...
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todo:paper_15417786_v13_n11_p1455_Labanca2023-10-03T16:22:55Z Association of HO-1 and BRCA1 is critical for the maintenance of cellular homeostasis in prostate cancer Labanca, E. De Luca, P. Gueron, G. Paez, A. Moiola, C.P. Massillo, C. Porretti, J. Giudice, J. Zalazar, F. Navone, N. Vazquez, E. De Siervi, A. BRCA1 protein cyclin D1 doxorubicin etoposide gelatinase B heme oxygenase 1 hydrogen peroxide methotrexate mitoxantrone transcription factor Nrf2 BRCA1 protein BRCA1 protein, human heme oxygenase 1 HMOX1 protein, human NFE2L2 protein, human protein binding transcription factor Nrf2 animal cell animal experiment animal model Article cancer cell controlled study DNA damage enzyme mechanism homeostasis human human cell immunofluorescence in vitro study in vivo study male mouse nonhuman oxidative stress priority journal promoter region prostate cancer prostate cancer cell line transcription initiation transcription regulation tumor xenograft animal genetics metabolism pathology prostate tumor tumor cell line xenograft Animals BRCA1 Protein Cell Line, Tumor DNA Damage Heme Oxygenase-1 Heterografts Humans Male Mice NF-E2-Related Factor 2 Oxidative Stress Prostatic Neoplasms Protein Binding Transcriptional Activation Prostate cancer is the second leading cause of cancer-related death in men worldwide. Many factors that participate in the development of prostate cancer promote imbalance in the redox state of the cell. Accumulation of reactive oxygen species causes injury to cell structures, ultimately leading to cancer development. The antioxidant enzyme heme oxygenase 1 (HMOX1/HO-1) is responsible for the maintenance of the cellular homeostasis, playing a critical role in the oxidative stress and the regulation of prostate cancer development and progression. In the present study, the transcriptional regulation of HO-1 was investigated in prostate cancer. Interestingly, the tumor suppressor BRCA1 binds to the HO-1 promoter and modulates HO-1, inducing its protein levels through both the increment of its promoter activity and the induction of its transcriptional activation. In addition, in vitro and in vivo analyses show that BRCA1 also controls HO-1-negative targets: MMP9, uPA, and Cyclin D1. HO-1 transcriptional regulation is also modulated by oxidative and genotoxic agents. Induction of DNA damage by mitoxantrone and etoposide repressed HO-1 transcription, whereas hydrogen peroxide and doxorubicin induced its expression. Xenograft studies showed that HO-1 regulation by doxorubicin also occurs in vivo. Immunofluorescence analysis revealed that BRCA1 overexpression and/or doxorubicin exposure induced the cytoplasmic retention of HO-1. Finally, the transcription factor NRF2 cooperates with BRCA1 protein to activate HO-1 promoter activity. In summary, these results show that the activation of BRCA1-NRF2/HO-1 axis defines a new mechanism for the maintenance of the cellular homeostasis in prostate cancer. Implications: Oxidative and genotoxic stress converge on HO-1 transcriptional activity through the combined actions of BRCA1 and NRF2. © 2015 AACR. Fil:Gueron, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Moiola, C.P. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Porretti, J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Giudice, J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Vazquez, E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:De Siervi, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_15417786_v13_n11_p1455_Labanca |
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Universidad de Buenos Aires |
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I-28 |
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R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
BRCA1 protein cyclin D1 doxorubicin etoposide gelatinase B heme oxygenase 1 hydrogen peroxide methotrexate mitoxantrone transcription factor Nrf2 BRCA1 protein BRCA1 protein, human heme oxygenase 1 HMOX1 protein, human NFE2L2 protein, human protein binding transcription factor Nrf2 animal cell animal experiment animal model Article cancer cell controlled study DNA damage enzyme mechanism homeostasis human human cell immunofluorescence in vitro study in vivo study male mouse nonhuman oxidative stress priority journal promoter region prostate cancer prostate cancer cell line transcription initiation transcription regulation tumor xenograft animal genetics metabolism pathology prostate tumor tumor cell line xenograft Animals BRCA1 Protein Cell Line, Tumor DNA Damage Heme Oxygenase-1 Heterografts Humans Male Mice NF-E2-Related Factor 2 Oxidative Stress Prostatic Neoplasms Protein Binding Transcriptional Activation |
| spellingShingle |
BRCA1 protein cyclin D1 doxorubicin etoposide gelatinase B heme oxygenase 1 hydrogen peroxide methotrexate mitoxantrone transcription factor Nrf2 BRCA1 protein BRCA1 protein, human heme oxygenase 1 HMOX1 protein, human NFE2L2 protein, human protein binding transcription factor Nrf2 animal cell animal experiment animal model Article cancer cell controlled study DNA damage enzyme mechanism homeostasis human human cell immunofluorescence in vitro study in vivo study male mouse nonhuman oxidative stress priority journal promoter region prostate cancer prostate cancer cell line transcription initiation transcription regulation tumor xenograft animal genetics metabolism pathology prostate tumor tumor cell line xenograft Animals BRCA1 Protein Cell Line, Tumor DNA Damage Heme Oxygenase-1 Heterografts Humans Male Mice NF-E2-Related Factor 2 Oxidative Stress Prostatic Neoplasms Protein Binding Transcriptional Activation Labanca, E. De Luca, P. Gueron, G. Paez, A. Moiola, C.P. Massillo, C. Porretti, J. Giudice, J. Zalazar, F. Navone, N. Vazquez, E. De Siervi, A. Association of HO-1 and BRCA1 is critical for the maintenance of cellular homeostasis in prostate cancer |
| topic_facet |
BRCA1 protein cyclin D1 doxorubicin etoposide gelatinase B heme oxygenase 1 hydrogen peroxide methotrexate mitoxantrone transcription factor Nrf2 BRCA1 protein BRCA1 protein, human heme oxygenase 1 HMOX1 protein, human NFE2L2 protein, human protein binding transcription factor Nrf2 animal cell animal experiment animal model Article cancer cell controlled study DNA damage enzyme mechanism homeostasis human human cell immunofluorescence in vitro study in vivo study male mouse nonhuman oxidative stress priority journal promoter region prostate cancer prostate cancer cell line transcription initiation transcription regulation tumor xenograft animal genetics metabolism pathology prostate tumor tumor cell line xenograft Animals BRCA1 Protein Cell Line, Tumor DNA Damage Heme Oxygenase-1 Heterografts Humans Male Mice NF-E2-Related Factor 2 Oxidative Stress Prostatic Neoplasms Protein Binding Transcriptional Activation |
| description |
Prostate cancer is the second leading cause of cancer-related death in men worldwide. Many factors that participate in the development of prostate cancer promote imbalance in the redox state of the cell. Accumulation of reactive oxygen species causes injury to cell structures, ultimately leading to cancer development. The antioxidant enzyme heme oxygenase 1 (HMOX1/HO-1) is responsible for the maintenance of the cellular homeostasis, playing a critical role in the oxidative stress and the regulation of prostate cancer development and progression. In the present study, the transcriptional regulation of HO-1 was investigated in prostate cancer. Interestingly, the tumor suppressor BRCA1 binds to the HO-1 promoter and modulates HO-1, inducing its protein levels through both the increment of its promoter activity and the induction of its transcriptional activation. In addition, in vitro and in vivo analyses show that BRCA1 also controls HO-1-negative targets: MMP9, uPA, and Cyclin D1. HO-1 transcriptional regulation is also modulated by oxidative and genotoxic agents. Induction of DNA damage by mitoxantrone and etoposide repressed HO-1 transcription, whereas hydrogen peroxide and doxorubicin induced its expression. Xenograft studies showed that HO-1 regulation by doxorubicin also occurs in vivo. Immunofluorescence analysis revealed that BRCA1 overexpression and/or doxorubicin exposure induced the cytoplasmic retention of HO-1. Finally, the transcription factor NRF2 cooperates with BRCA1 protein to activate HO-1 promoter activity. In summary, these results show that the activation of BRCA1-NRF2/HO-1 axis defines a new mechanism for the maintenance of the cellular homeostasis in prostate cancer. Implications: Oxidative and genotoxic stress converge on HO-1 transcriptional activity through the combined actions of BRCA1 and NRF2. © 2015 AACR. |
| format |
JOUR |
| author |
Labanca, E. De Luca, P. Gueron, G. Paez, A. Moiola, C.P. Massillo, C. Porretti, J. Giudice, J. Zalazar, F. Navone, N. Vazquez, E. De Siervi, A. |
| author_facet |
Labanca, E. De Luca, P. Gueron, G. Paez, A. Moiola, C.P. Massillo, C. Porretti, J. Giudice, J. Zalazar, F. Navone, N. Vazquez, E. De Siervi, A. |
| author_sort |
Labanca, E. |
| title |
Association of HO-1 and BRCA1 is critical for the maintenance of cellular homeostasis in prostate cancer |
| title_short |
Association of HO-1 and BRCA1 is critical for the maintenance of cellular homeostasis in prostate cancer |
| title_full |
Association of HO-1 and BRCA1 is critical for the maintenance of cellular homeostasis in prostate cancer |
| title_fullStr |
Association of HO-1 and BRCA1 is critical for the maintenance of cellular homeostasis in prostate cancer |
| title_full_unstemmed |
Association of HO-1 and BRCA1 is critical for the maintenance of cellular homeostasis in prostate cancer |
| title_sort |
association of ho-1 and brca1 is critical for the maintenance of cellular homeostasis in prostate cancer |
| url |
http://hdl.handle.net/20.500.12110/paper_15417786_v13_n11_p1455_Labanca |
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