showed that valproic acid potentiated the sensitivity of prostate cancer selleck inhibitor cells to cisplatin through down regulation of HR repair and DNA damage response genes such as BRCA1. The decrease in BRCA1 gene transcription was due to a reduction in binding of the activating protein, E2F1, to the BRCA1 promoter. In the same prostate cancer cell line model, a new HDAC inhibitor, H6CAHA, sup pressed the expression of BRCA1 mRNA, and when used in combination with g radiation, prevented the growth of tumor xenografts. The sensitizing properties of HDAC inhibitors to DNA damaging agents has been linked to aberrant dou ble strand break repair and cellular stress signaling. The present study confirms reports that HDAC inhibi tion, in combination with DNA damaging agents, increases the phosphorylation of H2A.

X, a known mar ker of DNA double strand breaks. A study con ducted in a metastatic breast cancer cell line provides evidence of increased phosphorylation of H2A. X and enhanced sensitivity to vorinostat in combination with radiation. In both human glioma and prostate can cer cells, vorinostat reduced DNA dependent protein kinase and Rad 51, two critical components of DNA double strand break repair machinery. In the human melanoma cell line, A375, vorinostat sensi tized cells to radiation induced apoptosis by inhibiting key DNA repair genes, Ku70, Ku80 and Rad 50. Using cDNA expression arrays, phenylbutyrate attenu ated the expression of DNA PK and worked synergisti cally with ionizing radiation to induce apoptosis in prostate cancer cell lines.

BRCA1 has many diverse functions in the cell includ ing transcriptional control through modulation of chro matin structure as BRCA1 is known to interact with the SWI/SNF chromatin remodeling complex. The BRCA1 SWI/SNF complex is believed to be essential for the activation of genes involved in the DNA damage response and this complex has a direct role in HR by enabling access to sites of DNA damage. The BRCA1 C terminal domain of the BRCA1 protein associ ates with both HDAC1 and HDAC2, and prior studies suggest that this association directly represses transcrip tion. In this study, the ChIP assay demonstrated that the amount of BRCA1 promoter DNA containing acetylated histones was decreased following M344 and cisplatin combination treatment relative to controls.

This result suggests that BRCA1 is not a direct target of M344 activity, but that M344 may enhance the expres sion or activity of a transcriptional repressor of BRCA1. As an example, the Inhibitor of DNA binding 4 is a dominant negative transcriptional regulator, which has been shown to repress the BRCA1 promoter. Studies have identified an inverse correlation between ID4 and BRCA1 mRNA and protein AV-951 expression levels in breast and ovarian tumour tissue. Further studies are needed to evaluate ID4s role in BRCA1 transcrip tional activity and as a potential marker of BRCA1 expression.