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

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. Androgen receptor (AR) ChIP-seq was carried out in LNCaP Talen Control, Bag-1L KO, Bag-1L KO plus Vector (control), Bag-1L KO plus (wild-type) Bag-1L, LNCaP plus wild-type Bag-1L and LNCaP plus CMut Bag-1L cells. Cells were cultured under hormone-starvation conditions for 72 h and then treated with vehicle (ETOH) or 10 nM DHT for 4 h prior to cell fixation and harvest. Experiments in LnCaP Talen Control and Bag-1L KO cells were carried out in duplicate.