Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [RNA-Seq KO]

Targeting the activation function-1 (AF-1) at the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the BAG domain of the cochaperone Bag-1L. Mutations in this domain or loss of Bag-1L abrogates AR signaling and reduces PCa growth. Correspondingly, Bag-1L protein levels increase with progression of primary prostate tumors to castration-resistant PCa, correlating inversely with patient response to abiraterone therapy. Intriguingly, BAG domain residues important for its interaction with the AR AF-1 overlap a potentially druggable pocket of this protein. Bag-1L is therefore a putative therapeutic target for the inhibition of AR AF-1 activity. Overall design: We performed transcriptome analysis (RNA-Seq) of 2 cell lines (LNCaP-Talen Control and LNCaP-Talen Bag1L KO) cultured in full medium (FM), or under hormone-starvation conditions for 72 h and then treated with vehicle (ethanol, EtOH) or 10 nM Dihydrotestosterone (DHT) for 16 h. Biological duplicate samples were analyzed for each cell line and each treatment condition.