The androgen receptor messenger RNA: what do we know?

Abstract

The Androgen Receptor (AR), transcriptionally activated by its ligands, testosterone and dihydrotestosterone (DHT), is widely expressed in cells and tissues, influencing normal biology and disease states. The protein product of the AR gene is involved in the regulation of numerous biological functions, including the development and maintenance of the normal prostate gland and of the cardiovascular, musculoskeletal and immune systems. Androgen signalling, mediated by AR protein, plays a crucial role in the development of prostate cancer (PCa), and is presumed to be involved in other cancers including those of the breast, bladder, liver and kidney. Significant research and reviews have focused on AR protein function; however, inadequate research and literature exist to define the function of AR mRNA in normal and cancer cells. The AR mRNA transcript is nearly 11 Kb long and contains a long 3' untranslated region (UTR), suggesting its biological role in post-transcriptional regulation, consequently affecting the overall functions of both normal and cancer cells. Research has demonstrated that many biological activities, including RNA stability, translation, cellular trafficking and localization, are associated with the 3' UTRs of mRNAs. In this review, we describe the potential role of the AR 3' UTR and summarize RNA-binding proteins (RBPs) that interact with the AR mRNA to regulate post-transcriptional metabolism. We highlight the importance of AR mRNA as a critical modulator of carcinogenesis and its important role in developing therapy-resistant prostate cancer.

Keywords: AR mRNA; Androgen receptor; RNA-binding proteins; prostate cancer; untranslated region.

Figure 1.

Androgen Receptor gene, mRNA and protein structure. (a, b) The AR gene is located on the X chromosome and consists of eight exons (E1-8) and seven variable size introns. (c) The AR mRNA is nearly 10.7 kb long, containing a 1.126 kb long 5’ UTR, a 6.778 kb long 3’ UTR and a 2.7 kb long coding region. (d) The AR protein consists of multiple functional domains: N-terminal domain (NTD), DNA-binding domain (DBD), Hinge region and C-terminal domain (CTD)/Ligand-binding domain (LBD). The N-terminal domain contains two transcriptional activation units (TAU) imperative for AR function.

Figure 2.

Androgen and cellular signalling alterations observed in AR-mediated transcriptional pathways during therapy resistance. (a) In the classical pathway, androgens such as Testosterone (T) present in the cytoplasm are converted to the highly potent Dihydrotestosterone (DHT) in the presence of 5-α reductase. DHT then binds to AR, inducing conformational changes, which results in the release of heat-shock proteins, followed by dimerization and translocation to the nucleus. In the nucleus, AR binds to Androgen response elements (AREs) and regulates the expression of AR target genes, and consequently the growth and survival of the cell. During PCa progression, changes in AR, such as AR splice variants, especially AR-V7 (b), and AR mutations (c), influence AR’s response to alternative ligands which can activate the AR signalling cascade, promoting the development of castration-resistant prostate cancer.

Figure 3.

RNA-binding proteins that interact with the Androgen Receptor mRNA. (a) Various RNA-binding proteins including DDX3, EBP1, HuR, PCBP1/2 and MSI2 interact with AR mRNA within the 5ʹUTR, ORF and 3ʹUTR to control translation and stability. (b) Splicing factors including U2AF65 and hnRNP1 interact with an intronic splicing enhancer (ISE) while Sam68 and ASF/SF2 interact with an exonic splicing enhancer (ESE) located within the 3’ splice site of exon 3b. This results in cryptic exon splicing and generation of AR-V7 variant. PSF is predicted to bind within intron 3. (c) mRNA structure of AR-V7 lacking exons 5 through 8 (the ligand binding domain).