title: Association of HO-1 and BRCA1 Is Critical for the Maintenance of Cellular Homeostasis in Prostate Cancer.
abstract: 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.
  
  
  CONCLUSIONS
  Oxidative and genotoxic stress converge on HO-1 transcriptional activity through the combined actions of BRCA1 and NRF2.
authors.affiliation: Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biologia y Medicina Experimental (IBYME)-CONICET, Buenos Aires, Argentina. Laboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Labanca
authors.affiliation: Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biologia y Medicina Experimental (IBYME)-CONICET, Buenos Aires, Argentina.
authors.forename: Paola
authors.initials: P
authors.lastname: De Luca
authors.affiliation: Laboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Gueron
authors.affiliation: Laboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Paez
authors.affiliation: Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biologia y Medicina Experimental (IBYME)-CONICET, Buenos Aires, Argentina.
authors.forename: Cristian P
authors.initials: CP
authors.lastname: Moiola
authors.affiliation: Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biologia y Medicina Experimental (IBYME)-CONICET, Buenos Aires, Argentina.
authors.forename: Cintia
authors.initials: C
authors.lastname: Massillo
authors.affiliation: Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biologia y Medicina Experimental (IBYME)-CONICET, Buenos Aires, Argentina.
authors.forename: Juliana
authors.initials: J
authors.lastname: Porretti
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
authors.forename: Jimena
authors.initials: J
authors.lastname: Giudice
authors.affiliation: Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biologia y Medicina Experimental (IBYME)-CONICET, Buenos Aires, Argentina.
authors.forename: Florencia
authors.initials: F
authors.lastname: Zalazar
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Nora
authors.initials: N
authors.lastname: Navone
authors.affiliation: Laboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Elba
authors.initials: E
authors.lastname: Vazquez
authors.affiliation: Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biologia y Medicina Experimental (IBYME)-CONICET, Buenos Aires, Argentina. adrianadesiervi@gmail.com.
authors.forename: Adriana
authors.initials: A
authors.lastname: De Siervi
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D015533:Transcriptional Activation
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1