We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy (ADT) synergizes with ionizing radiation (IR). Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output which correlates with expression of a set of DNA repair genes. Employing RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with IR plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical non-homologous end joining.

<p>Supplementary Table S1 - PDF file 170K, Gene set enrichment analysis of ARN-509-treated LNCaP-AR xenografts</p>

<p>Supplementary Figure S4 - PDF file 793K, Immunoblot of LNCaP demonstrating LIG4 knockdown</p>

<p>Supplementary Table S2 - PDF file 250K, Defining AR-regulated DNA repair genes in LNCaP</p>

<p>Supplementary Figure S1 - PDF file 1194K, Gamma-H2AX foci and Comet assay normalized of LNCaP plus or minus androgen normalized to time 0</p>

<p>Supplementary Figure S2 - PDF file 1705K, LNCaP cell cycle distribution by PI and BrdU analyses plus or minus androgen</p>

<p>Supplementary Figure S3 - PDF file 1337K, LNCaP cell cycle distribution by PI and BrdU analyses plus or minus ARN-509</p>

<p>Supplementary Figure S1 - PDF file 1194K, Gamma-H2AX foci and Comet assay normalized of LNCaP plus or minus androgen normalized to time 0</p>