Androgen receptor co-regulation in prostate cancer

Prostate cancer (PCa) progression relies on androgen receptor (AR) action. Preventing AR's ligand-activation is the frontline treatment for metastatic PCa. Androgen deprivation therapy (ADT) that inhibits AR ligand-binding initially induces remission but eventually fails, mainly because of adaptive PCa responses that restore AR action. The vast majority of castration-resistant PCa (CRPC) continues to rely on AR activity. Novel therapeutic strategies are being explored that involve targeting other critical AR domains such as those that mediate its constitutively active transactivation function, its DNA binding ability, or its interaction with co-operating transcriptional regulators. Considerable molecular and clinical variability has been found in AR's interaction with its ligands, DNA binding motifs, and its associated coregulators and transcription factors. Here, we review evidence that each of these levels of AR regulation can individually and differentially impact transcription by AR. In addition, we examine emerging insights suggesting that each can also impact the other, and that all three may collaborate to induce gene-specific AR target gene expression, likely via AR allosteric effects. For the purpose of this review, we refer to the modulating influence of these differential and/or interdependent contributions of ligands, cognate DNA-binding motifs and critical regulatory protein interactions on AR's transcriptional output, which may influence the efficiency of the novel PCa therapeutic approaches under consideration, as co-regulation of AR activity.