Highlights d ARfl and ARv7 genomic binding is interdependent and colocalized d ARv7, unlike ARfl, preferentially represses transcription d Expression of ARv7-repressed genes negatively correlates with recurrence d Re-expression of ARv7-repressed genes may serve as a biomarker of ARv7 inhibition

Targeting the activation function-1 (AF-1) domain located in 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 cochaperone Bag-1L. Mutations in the AR interaction domain or loss of Bag-1L abrogate AR signaling and reduce PCa growth. Clinically, Bag-1L protein levels increase with progression to castration-resistant PCa (CRPC) and high levels of Bag-1L in primary PCa associate with a reduced clinical benefit from abiraterone when these tumors progress. Intriguingly, residues in Bag-1L important for its interaction with the AR AF-1 are within a potentially druggable pocket, implicating Bag-1L as a potential therapeutic target in PCa.

Androgens are important determinants of normal and malignant prostate growth. They function by binding to the C-terminal ligand-binding domain (LBD) of the androgen receptor (AR). All clinically approved AR-targeting antiandrogens for prostate cancer therapy function by competing with endogenous androgens. Despite initial robust responses to androgen deprivation therapy, nearly all patients with advanced prostate cancer relapse with lethal castration-resistant prostate cancer (CRPC). Progression to CRPC is associated with ongoing AR signaling, which in part, is due to the expression of constitutively active AR splice variants that contain the N-terminus of the receptor but lack the C-terminus. Currently, there are no approved therapies specifically targeting the AR N-terminus. Current pharmacologic targeting strategies for inhibiting the AR N-terminal region have proven difficult, due to its intrinsically unstructured nature and lack of enzymatic activity. An alternative approach is to target key molecules such as the cochaperone BAG1L that bind to and enhance the activity of the AR AF1. Here, we review recent literature that suggest Bag-1L is a promising target for AR-positive prostate cancer.