Different doses of androgens induce the expression of distinct gene expression programs (ATAC-Seq)
Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Paradoxically, high dose androgens have also shown considerable efficacy in the treatment of patients with late-stage metastatic PCa. In probing the mechanisms that enable cells to recognize and respond to different levels of the same hormone, it was determined that low levels of androgens, functioning through an AR monomer, facilitates a non-genomic activation of the mTOR signaling pathway to drive proliferation. Conversely, high dose androgens facilitate the formation of AR dimers to suppress c-MYC expression, inhibit proliferation and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR action in PCa and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies. Overall design: To identify molecular events responsible for the non-linear proliferative responses to androgens, we performed an unbiased genome-wide survey of changes in chromatin accessibility with the goal of identifying potential cis-acting elements enriched in LD versus HD treated PCa cells. To this end, we performed an assay for transposase-accessible chromatin using sequencing (ATAC-seq) in both VCaP and LNCaP cells following treatment with vehicle, increasing concentrations of low-dose 0.01, 0.03, 0.06, 0.1 nM R1881) or High-Dose (10nM R1881) androgens for 24 hrs.