Hypoxia-independent gene expression signature associated with radiosensitisation of prostate cancer cell lines by histone deacetylase inhibition. Homo sapiens

We aimed to investigate gene expression associated with radiosensitisation of normoxic and hypoxic prostate cancer cells by the class I/II histone deacetylase inhibitor (HDACi) vorinostat. A pronounced deregulation of DNA repair and chromatin organization genes by vorinostat in DU 145 than in PC-3 or 22Rv1 was found and was a likly mechanism underlying radiosensitisation of DU 145. Expression of these genes was generally not affected by hypoxia and was altered by vorinostat in DU 145 towards the baseline levels of PC-3 and 22Rv1. A 56-gene expression signature associated with radiosensitisation under normoxia and hypoxia, including 8 genes with baseline expression characteristic of the radiosensitising effect was generated. These findings propose a hypoxia independent expression signature to predict the radiosensitising effect of vorinostat. Overall design: DU 145, PC-3 and 22Rv1 cell lines, for which differences in intrinsic radiosensitivity have been demonstrated in previous work, were exposed to vorinostat (1µM, 24h) and hypoxia (0.2% O2, 24h), subjected to gene expression profiling and irradiated at 2 and 5 Gy. Samples collected for gene expression analysis were taken prior to irradiation. Vorinostat mediated radiosensitisation occurred under normoxia and hypoxia in the intrinsically radioresistant DU 145, but not in the radiosensitive PC-3 and 22Rv1. To identify a gene expression signature most likely playing a major role in the vorinostat mediated radiosensitisation, a supervised analysis of global gene expression data were performed.