Cooperativity and Equilibrium with FOXA1 Define the Androgen Receptor Transcriptional Program

The pioneering factor FOXA1 opens chromatin to facilitate androgen receptor (AR) binding to prostate-specific genes. How FOXA1 controls the AR cistrome, however, is incompletely understood. Here we show that AR directly binds chromatin through the androgen-response elements (AREs). FOXA1 is not required for AR-chromatin interaction, but instrumental in recruiting AR to low-affinity half-AREs by opening local chromatin around adjacent FKHD sites. Too much FOXA1 creates excessive open chromatin regions, which serve as reservoirs that retain AR via abundant half-AREs, thereby reducing its availability for specific sites. FOXA1 down-regulation, by contrast, relinquishes AR to permissively bind AREs across the genome, resulting in substantial AR binding events and AR-target gene expression even in the absence of androgen. Taken together, our data illustrate the mechanistic details by which cooperativity and equilibrium with FOXA1 define AR cistrome and reveal a previously unknown function of FOXA1 in inhibiting AR signaling and castration-resistant prostate cancer growth.