Intriguingly androgens may also have an
Intriguingly androgens may also have an indirect effect on AR gene expression through inhibition of the GATA2 transcription factor gene (He et al., 2014) (Table 1). Using ChIP-seq, GATA2 was found to bind to a regulatory element 5.5 kb upstream of the TSS of the AR gene and enhanced transcription, while treatment of prostate Clonidine HCl mg with an AR agonist led to repression of both GATA2 and AR mRNA (He et al., 2014). In addition, a GATA2 binding site downstream of the TSS at +762 has also been correlated with positive regulation of the AR gene (Wu et al., 2014) (Fig. 2).
AR expression in bone The AR is expressed in both bone forming osteoblasts and bone remodelling osteoclasts (Vanderschueren et al., 2004, Manolagas et al., 2013). The actions of androgens in bone are complex involving both direct, AR-mediated, and indirect, oestrogen receptor α (ERα) action. DHT has been shown to increase expression of the receptor mRNA (Wiren et al., 1997). The response was mapped to a 3 kb stretch of DNA encompassing the promoter and part of the 5′UTR (−2330 to +573) (Wiren et al., 1997). In the same osteoblast cell-line, SaOS-2, derived from an 11 year old girl, we also observe an increase in receptor mRNA in response to DHT treatment (Fig. 3). The use of DHT in both studies would support this regulation being a direct action of the AR. However, binding of the AR to sequences within the putative regulatory region has not be demonstrated. The outstanding question concerns the mechanism(s) involved in this upregulation and how this compares with the reported down–regulation observed in other cells, notably prostate and breast. Importantly, not all AREs in the hAR gene are inhibitory and early studies have suggested that the AR can enhance expression of the receptor message through a composite binding site spanning exons 4 and 5 (Reviewed in Burnstein, 2005). The AREs furthest from the promoter are somewhat unusual in that the half sites lie in two exons (4 and 5) separated by a 5790 bp intron (Dai and Burnstein, 1996) and together with Myc, upregulate AR transcription (Grad et al., 1999) (Fig. 2). Two other non-consensus AREs are also present and these bind AR much more weakly in EMSA studies, but are required for maximal androgen regulation. Myc has been shown to directly upregulate hAR expression by binding to a consensus E box in exon 4 at +167,636 bp (Grad et al., 1999) (Fig. 2). Bound Myc interacts with its binding partner Max via a basic helix-loop-helix leucine zipper domain and both proteins are required for AR stimulation of the AREs in exons 4 and 5 described above. Interestingly, the expression of Myc is repressed by androgens in the prostate cancer cell line LNCaP (Bolton et al., 2007) and upregulated by oestrogen (17β-estradiol) in breast cancer cells (Cicatiello et al., 2004).
AR expression and ageing Rats and mice maintained on calorie restricted diets have demonstrably longer life spans (Guarente, 2013). It is therefore interesting that a calorie restricted diet can rescue the down-regulation of the AR mRNA in the ageing rat liver (Song et al., 1991). The regulatory sequences mediating the age-dependent down-regulation of the rat AR were mapped to the promoter of the receptor gene, and termed ‘age-dependent factor’ (ADF: −301 to −330 bp) and ‘associated factor’ (AF: −340 to −372) (Supakar et al., 1993). Loss of binding at these elements was associated with aging in the rat liver. Further work from the Chatterjee laboratory, identified the composition of the transcription factor complexes binding to the ADF element, which included the proto-oncoproteins B-Myb and/or c-Myb associated with either PARP-1 and hnRNPK (activation) or p53 and a co-repressor complex (repression) (Shi et al., 2008) (Table 1). Furthermore, the transcriptional repression complex was correlated with down regulation of the AR gene in response to oxidative stress. However, the regulatory elements identified in the rat AR promoter do not appear to be conserved in the human gene.