Antagonism, Androgen receptor leads to Altered, Transcription of genes by AR

The fact that AR exert its primary function as a nuclear transcription factor is well-established and a generally accepted fact. Binding of androgens (ligands) to the AR induces receptor activation and transcriptional regulation of target genes (Chang et al, 1995; Davey & Grossmann, 2016; Heemers & Tindall, 2007). After binding to Androgen Response Elements (AREs), the AR can recruit a variety of co-regulators (activators or repressors) that will influence the transcriptional regulation of target genes and thereby achieve spatiotemporally regulated gene expression (Heemers & Tindall, 2007). Consequently, inhibition/competition of ligand binding to the AR leading to reduced activity will have an effect on downstream transcriptional function.

The activation of AR by ligand binding is crucial for transcriptional activation of target genes. Thus, antagonism of AR (upstream KE) will have a direct effects on nuclear translocation and subsequent transcriptional activation of target genes (downstream KE). There is ample evidence showing that AR regulate gene expression in a large number of cells and tissues across animal species, as well as altered gene expression following ectopic activation or antagonisms of AR (Grosse et al, 2012; Lamb et al, 2014; Lamont & Tindall, 2010; Matsumoto et al, 2013; Mikkonen et al, 2010; Olsen et al, 2016). Below are examples of evidence for AR antagonism leading to altered gene transactivation (assay) or expression of gene targets in cells and tissues. The list is not exhaustive.

• There are several drugs that bind the AR ligand binding domain in competition to androgens (testosterone and DHT), thereby inhibiting AR nuclear translocation and transcriptional activation, for instance flutamide (Irwin & Prout Jr, 1973), biculamide (Furr, 1988), enzalutamide (Tran et al, 2009) and darolutamide (Moilanen et al, 2015).  
• Exploiting well-characterized AR response elements (AREs), several in vitro AR reporter (transactivation) assays have been developed, and reported on extensively in the scientific literature. These study show direct antagonistic effects of a large number of compounds on the AR, with several examples listed under KE 26.
• Using ChIP and DNA/RNA sequencing technologies, a complex network of genes directly regulated by AR has been mapped in for instance prostate cancer cells (Takayam & Inoue, 2013).
• Plumagin, a naphthoquinone, can inhibit DHT-mediated AR-regulated gene expression in prostate cancer cells, shown by RNA-seq analysis (Rondeau et al, 2018).
• Short-term exposure to the AR antagonists flutamide and vinclozolin significantly alters the gonadal transcriptome in mature zebrafish (Martinović-Weigelt et al, 2011)
• In utero exposure to rats to the AR antagonist finasteride alters the transcriptome in male perineal tissues (Schwartz et al, 2019).
• Genome-wide analysis of AR target genes in mesenchymal cells during human prostate development has shown variable expression of AR target genes in androgen insensitivity syndrome patients (Nash et al, 2019).
• Human LNCaP prostate cancer cells stimulated for 24h with the AR agonist R1881 display up- and down-regulation of around 300 genes in both directions (Ngan et al, 2009).

The AR gene contains CAG repeats (encoding for the amino acid glutamine), which vary between individuals and will affect transcriptional function. Broadly speaking, fewer CAG repeats tend to render the AR more sensitive to androgen activation whereas more CAG repeats tend to render the AR less sensitive, albeit the functional relevance at the tissue/organ level remains less clear (Tirabassi et al, 2015; Zitzmann, 2009). It is plausible, however, that it may lead to variable sensitivity to AR antagonism.