Androgen receptor-mediated assisted loading of the glucocorticoid receptor modulates transcriptional responses in prostate cancer cells (ATAC-seq)

Steroid receptors are involved in a wide array of crosstalk mechanisms that regulate diverse biological processes, with significant implications in diseases, particularly in cancers. In prostate cancer, indirect crosstalk between androgen receptor (AR) and glucocorticoid receptor (GR) is well-documented, where GR replaces antiandrogen inactivated AR becoming the disease driver. However, the existence and impact of direct chromatin crosstalk between AR and GR in prostate cancer have remained elusive. Our genome-wide investigations reveal that AR activation significantly expands GR chromatin binding. Mechanistically, AR induces remodeling of closed chromatin sites, facilitating GR binding to normally inaccessible sites. Importantly, coactivation of AR and GR results in distinct transcriptional responses at both the population and single-cell levels. Intriguingly, genes and pathways affected by these transcriptional changes are generally associated with improved patient survival. Thus, the direct crosstalk between AR and GR yields markedly different outcomes from the known role of GR in circumventing AR blockade by antiandrogens.