Association of HO-1 and BRCA1 Is Critical for the Maintenance of Cellular Homeostasis in Prostate Cancer

LABANCA, ESTEFANIA; DE LUCA, PAOLA; GUERON, GERALDINE; PAEZ, ALEJANDRA VERÓNICA; MOIOLA, CRISTIAN; MASILLO, CINTIA; PORRETTI, JULIANA; GIUDICE, JIMENA; ZALAZAR FLORENCIA; NAVONE, NORA; VAZQUEZ, ELBA SUSANA; DE SIERVI, ADRIANA

MOLECULAR CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2015

1541-7786

Prostate cancer is the second leading cause of cancer-relateddeath in men worldwide. Many factors that participate in thedevelopment of prostate cancer promote imbalance in the redoxstate of the cell. Accumulation of reactive oxygen species causesinjury to cell structures, ultimately leading to cancer development.The antioxidant enzyme heme oxygenase 1 (HMOX1/HO-1) isresponsible for the maintenance of the cellular homeostasis,playing a critical role in the oxidative stress and the regulationof prostate cancer development and progression. In the presentstudy, the transcriptional regulation of HO-1 was investigated inprostate cancer. Interestingly, the tumor suppressor BRCA1 bindsto the HO-1 promoter and modulates HO-1, inducing its proteinlevels through both the increment of its promoter activity and theinduction of its transcriptional activation. In addition, in vitro andin vivo analyses show that BRCA1 also controls HO-1?negativetargets: MMP9, uPA, and Cyclin D1. HO-1 transcriptional regulationis also modulated by oxidative and genotoxic agents.Induction of DNA damage by mitoxantrone and etoposiderepressed HO-1 transcription, whereas hydrogen peroxide anddoxorubicin induced its expression. Xenograft studies showedthat HO-1 regulation by doxorubicin also occurs in vivo. Immunofluorescenceanalysis revealed that BRCA1 overexpressionand/or doxorubicin exposure induced the cytoplasmic retentionof HO-1. Finally, the transcription factor NRF2 cooperates withBRCA1 protein to activate HO-1 promoter activity. In summary,these results show that the activation of BRCA1?NRF2/HO-1 axisdefines a new mechanism for the maintenance of the cellularhomeostasis in prostate cancer.