Interdependent androgen and glucocorticoid receptor signalling shapes prostate epithelial homeostasis

Androgen signalling is essential for prostate secretory functions and epithelial cell maintenance, yet how this signal is translated into a transcription output remains poorly understood. Androgens functions are primarily mediated by the androgen receptor (AR) that binds hormone response elements similar to those of other steroid receptors, including the glucocorticoid receptor (GR). Here we show that AR and GR are co-expressed in the prostate epithelium, and located within nuclear foci. Moreover, GR promotes the formation and dynamics of AR nuclear condensates, and heterodimerizes with AR in a ligand binding domain-dependent manner. In addition, subtle variations within the hormone response element sequence direct the co-recruitment of AR and GR within activator or repressor complexes to activate or repress gene expression. Finally, prostate-specific deletion of GR in mice disrupts AR nuclear distribution, impairs AR-dependent gene networks involved in epithelial maintenance, and promotes the expression of genes involved metabolism and cell cycle, resulting in altered tissue homeostasis. Thus, these findings identify GR as an integral component of the AR transcriptional machinery in epithelial cells of the healthy prostate, and reveal how shared cis-regulatory elements are interpreted to generate distinct transcriptional outcomes.