Androgen receptor co-regulation in prostate cancer

Abstract

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.

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

“…Coregulators are not DNA-binding proteins, but are recruited to transcription factors, such as the AR, and have different activities involved in the regulation of gene expression; some of them cause chromatin reconfiguration or are needed to bind some other cofactors [ 19 ].…”

“…Bisphenol A, as an environmental endodisruptor, can bind AR and is considered a direct xeno-estrogen AR agonist. The participation of these environmental ligands, as well as individual mutations or expression levels of steroidogenic genes, may explain the inter-individual variability seen in the AR activity related to prostate cancer and other pathologies [ 19 ].…”

“…Once the AR dimer is bound to the DNA, it forms complexes with transcriptional coactivators and co-regulators for the regulation of target gene expression (Figure 1) [4,6,[14][15][16][17][18]. Coregulators are not DNA-binding proteins, but are recruited to transcription factors, such as the AR, and have different activities involved in the regulation of gene expression; some of them cause chromatin reconfiguration or are needed to bind some other cofactors [19].…”

Evolution of Hominin Detoxification: Neanderthal and Modern Human Ah Receptor Respond Similarly to TCDD

“…2006 ; Claessens et al. 2017 ; Senapati et al. 2020 ) and other nuclear receptors (NRs) ( Billas and Moras 2013 ; De Vera et al.…”

Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer

“…In general, it is suggested that the balance of co-activator and co-repressors is required for fine tuning AR-mediated transcription. A misbalance of the co-regulators can lead to higher AR activity in PCa and less active antagonism by anti-androgens [ 38 , 39 , 40 , 41 ].…”