Cooperativity and equilibrium with FOXA1 define the androgen receptor transcriptional program

Abstract

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.

Role of steroid receptor and coregulator mutations in hormone-dependent cancers

“…Therefore, FOXA1 inactivation may be an additional mechanism that influences AR-dependent transcription. In agreement with this, it has been proposed that decreased levels of FOXA1 significantly alter the AR cistrome (111).…”

ALDH1A3 correlates with luminal phenotype in prostate cancer

“…Fortunately, many preclinical studies or clinical trials have focused on AR-interacting proteins such as chaperones, 21,22 pioneer transcription factors, 23,24 and AR transcriptional coregulators. [25][26][27] Given the resistance from directly targeting AR, these novel AR-interacting proteins probably provide alternative therapeutic methods to overcome the resistance.…”

Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

“…More recently, the genomic binding profile of AR variants have also been explored and have been shown to compensate for full length AR in an endocrine therapy-like setting [22]. These studies have provided valuable insights in to the molecular biology and function of the AR and have identified several co-activators and corepressors that modulate AR transcriptional activity [23][24][25][26][27][28].…”