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    • Negative regulation of AR expression by NF B was also

    2023-01-24

    Negative regulation of AR expression by NFκB was also correlated with the ‘age-dependent desensitisation’ of androgen action in the rat liver (Supakar et al., 1995). In this case the binding site was mapped upstream of the gene to sequences −555 to −565 bp, that binds heterodimers of p65 and p50, as well as p50 homodimers (Fig. 2). The ratio of p50 homodimers to heterodimers increases 10 fold with age leading to recruitment of histone deacetylase leading to downregulation of the AR gene (Supakar et al., 1995). Using protein extracts from rat Sertoli cells an additional binding site was described at −482 to −491 bp (Delfino et al., 2003). In contrast to the liver, binding of NFκB was associated with stimulation of AR expression in Sertoli cells (Delfino et al., 2003, Zhang et al., 2004). NFκB has also been shown to strongly upregulate hAR promoter activity in LNCaP through the use of reporter gene assays (Zhang et al., 2009). The consensus binding sequence for NFκB incorporates a high degree of variability resulting in seven potential sites within the hAR promoter between approximately −1600 and + 1 (Fig. 2): and an eighth site greater than 3.2 kb upstream. ChIP analysis using antibody against the p50 subunit confirmed binding of NFκB to the promoter. However, as the average lengths of DNA fragments used in the ChIP assays was 1 kb, it is impossible to determine which of the potential sites are functional. However, a B-Myb binding site (+176 to +181) and associated NFκB element that lies three turns of the DNA helix (+145 to +154) have been delineated in the 5′UTR of the human AR gene (Ko et al., 2008) (Fig. 2). These sequences lie on the same face of the DNA double helix and form a composite regulatory element required for the negative regulation of AR mRNA by the proinflammatory cytokine, TNFα, in prostate calls (Fig. 2). B-Myb is expressed in virtually all proliferating cells where it is involved in alpha-Endorphin progression and is implicated in carcinogenesis and cellular senescence. As a transcription factor it can either stimulate or repress target genes, however, in the context of hAR transcription, the main function appears to be to stabilise binding of NFκB to its adjacent site and to participate in forming a multi-protein complex that includes histone deacetylase 1 (Ko et al., 2008). As a consequence, chromatin remodelling leads to downregulation of the hAR gene. It is also noteworthy that the binding of p53 to sequences upstream of the TSS, −488 to −469 bp, has been described in several human cell-lines, including prostate (PrECs, LNCaP), bone (SaOS-2) and human colorectal cells (HCT116) (Alimirah et al., 2007) (Fig. 2). The binding of p53 was associated with repression of AR mRNA transcription. p53 is activated in response to various forms of cell stress e.g. DNA damage, oxidative stress and hypoxia, and can either stimulate or repress target genes which are predominantly involved in cell cycle progression, apoptosis and DNA repair. Impaired functioning of the p53 pathway is a major factor in over half of all cancers, and mutations in the p53 gene (TP53) resulting in loss of function in prostate cancer are associated with tumour progression and poor prognosis (Burchardt et al., 2001, Heidenberg et al., 1995). These findings are consistent with loss of p53 suppression of hAR expression leading to high levels of AR. It will be important to determine if the action of p53 and B-Myb (and NFκB), cooperate in a manner analogous to their function on the rat promoter to regulate the human AR gene in an age-dependent manner.
    Androgens and the process of epithelial mesenchymal transition Epithelial mesenchymal transition (EMT) acts under different physiological conditions as a source of mesenchymal cells during development, tissue repair and fibrosis and cancer cell invasiveness and metastasis (Kalluri and Weinberg, 2009). In the context of AR expression and signalling, EMT has primarily been studied in terms of cancer progression and/or development of CRPC. Interestingly, two bHLH transcription factors, Twist 1 (Soini et al., 2011, Shiota et al., 2015) and ZEB1 (Martin et al., 2013), associated with the EMT response have been shown to regulate expression of the AR gene (Table 1).