BioProject

The mainstay treatment for men with metastatic prostate cancer is androgen deprivation therapy (ADT), which inhibits androgen biosynthesis and/or binding of ligand to the androgen receptor (AR). More...

The mainstay treatment for men with metastatic prostate cancer is androgen deprivation therapy (ADT), which inhibits androgen biosynthesis and/or binding of ligand to the androgen receptor (AR). Most men respond to ADT, but all subsequently develop resistance and progression to incurable and lethal castration-resistant prostate cancer (CRPC). CRPC generally remains driven by the AR: therefore, the development of novel AR-targeted therapies, as well as elucidating therapy-driven changes to the AR signalling axis that mediate resistance, remain priorities for the field. Using a novel and powerful proteomic technique, rapid immunoprecipitation of endogenous proteins (RIME), we have identified a new AR binding protein, the transcription factor Grainyhead-like 2 (GRHL2), and shown that it plays an essential, multifaceted role in signalling by the canonical AR and by constitutively active truncated AR variants (ARVs). GRHL2 is necessary for the maintenance of AR/ARV expression in multiple prostate cancer model systems, co-localises with AR at specific sites on chromatin to enhance the androgen-regulated transcriptional program, and is required for optimal prostate cancer growth. Interestingly, we found that GRHL2 is itself an AR/ARV-regulated gene, creating a positive feed-forward loop between the two factors. The GRHL2 gene is frequently amplified and upregulated in CRPC, thereby potentially enabling further amplification AR signalling in the drug-resistant setting. In summary, this study has identified a critical new AR coregulator and potential therapeutic target in prostate cancer. Overall design: RNA-seq following GRHL2 knockdown in LNCaP cells Less...