Androgen receptor drives divergent chromatin accessibility programs in benign and malignant prostate epithelial cells.

Androgen receptor (AR) activation alters chromatin structure in prostate cancer (PC) cells, but its impact in nonmalignant prostate epithelial cells (NPEC) remains poorly characterized due to lack of representative models. We leveraged our previously established NPEC (RWPE-1-AR and RWPE-1-Ctrl) and PC (LNCaP-pcDNA3.1 and LNCaP-ARhi) cell models to profile androgen-driven chromatin responses using assay for transposase-accessible chromatin with sequencing (ATAC-seq). In the absence of androgen, NPEC and PC cells exhibited widespread differences in chromatin accessibility. Androgen stimulation amplified these differences, revealing distinct AR-mediated chromatin remodeling between the cell types. Androgen-sensitive regions were enriched for nuclear receptor binding sites (AR and glucocorticoid receptor), with AP-1 motifs more prominent in NPEC and FOXA1 motifs in PC cells. Comparison with ATAC-seq profiles obtained from clinical samples showed that NPECs resembled benign prostate hyperplasia, while PC cells mirrored untreated and castration-resistant PC, supporting the relevance of our models. Integration of ATAC-seq and mRNA-sequencing (mRNA-seq) identified model-specific AR target genes, including CDKN1C/p57 in NPEC, which may contribute to the previously observed androgen-induced growth arrest in these cells. These findings demonstrate that AR activation reprograms chromatin accessibility in normal prostate epithelium, revealing fundamental regulatory differences compared to the tumor context and underscore the importance of physiologically relevant cell models.