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 CP; PORRETTI J; GIUDICE J; ZALAZAR F; NAVONE N; VAZQUEZ ES; DE SIERVI A

MOLECULAR CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2015 vol. 13 p. 1455 - 1464

1541-7786

Prostate cancer (PCa) is the second leading cause of cancer-related death in men worldwide. Many factors that participate in the development of PCa promote imbalance in the redox state of the cell. Accumulation of reactive oxygen species (ROS) 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 PCa development and progression. In the present study, the transcriptional regulation of HO-1 was investigated in PCa. 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, while 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 PCa.