BPTF regulates androgen receptor activity by enhancing chromatin accessibility and stabilizing the AR-FOXA1 interaction

Abstract BPTF, the scaffolding subunit of the nucleosome remodeling factor (NURF) complex, has been implicated in the progression of several malignancies, but its role in prostate cancer (PCa) remains unclear. Here, we demonstrate that BPTF is upregulated in castration-resistant prostate cancer (CRPC) and promotes disease progression. RNA-seq revealed that BPTF primarily enhances the expression of androgen receptor (AR) target genes. ChIP-seq showed that BPTF increases AR binding at promoters, enhancers and super-enhancers. ATAC-seq further demonstrated that BPTF increases chromatin accessibility to facilitate AR binding, in part through SMARCA1, a catalytic subunit of the NURF complex. Notably, BPTF/AR co-bound regions are highly enriched for FOXA1 motifs but only weakly enriched for AR motifs. We further show that BPTF forms a protein complex with AR and FOXA1, in which FOXA1 recruits the BPTF-AR complex to chromatin, while BPTF stabilizes the AR-FOXA1 interaction. Importantly, BPTF interacts with AR through its bromodomain, and a BPTF bromodomain inhibitor disrupts this interaction, impairs AR signaling and suppresses PCa cell growth. In summary, our findings establish BPTF as a critical regulator of AR activity by promoting chromatin accessibility and stabilizing the AR-FOXA1 complex, highlighting BPTF as a potential therapeutic target in prostate cancer.