Androgen receptor: Functional roles and facets of regulation in urology

The androgen receptor (AR) is a member of the steroid receptor family of transcription factors. These ligandregulated transcription factors have C-terminal ligand binding domains with low nanomolar affinities for their cognate steroid ligands. The steroid ligands for AR are the androgens testosterone and dihydrotestosterone (DHT),which are the most abundant sex hormones in the circulation of males.In the absence of androgens,AR is kept in an inactive conformation in the cytoplasm of target cells.Binding of androgens to the AR ligand binding domain induces a conformational change that exposes a nuclear localization signal, leading to translocation of AR to the nucleus. In the nucleus, AR binds as a dimer to genomic androgen response elements that are composed of inverted hexameric repeats. Binding of AR dimers to these DNA elements leads to nucleation of transcriptional complexes that consist of coregulatory proteins,other transcription factors,and components of the general transcriptional apparatus.Androgen response elements are located in promoter and distal enhancer elements of genes that are central regulators of a multitude of physiological processes. Accordingly,activation of the AR is tightly regulated by autocrine and paracrine signaling pathways, post-translational modifications, ligand milieu, coregulatory proteins, microRNAs,mRNA splicing, and cellular metabolism.

Regulation of AR expression and activity has been an area of intense research in the field of urology. AR plays a central role in normal development of the male urogenital system, as well as urogenital pathologies including benign prostatic hyperplasia (BPH), prostate cancer, as well as bladder cancer. Accordingly, AR represents an important drug target for medical management of these pathologies.For instance, treatment of BPH can involve the use of 5-alpha reductase inhibitors that block conversion of testosterone to DHT. The mainstay systemic treatment for prostate cancer involves inhibiting androgen production and/or treatment with antiandrogens that act as competitive antagonists of the AR ligand binding domain. There is also growing evidence that AR may represent a tractable therapeutic target in bladder cancer. The series of reviews invited for this issue ofAsian Journal of Urology (AJU)will cover the role and regulation of AR by diverse pathways in normal prostate development,benign pathologies including BPH, as well as prostate cancer and bladder cancer.

The first review is entitledThe role of the androgen receptor in prostate development and benign prostatic hyperplasia:A review,and is authored by Vickman,Franco,Moline, Vander Griend, Thumbikat, and Hayward. This article highlights the role of the AR in prostate development and provides evidence that altered expression and activity of stromal and epithelial AR is important for the development and progression of BPH.

The second review is entitledPosttranslational regulation of androgen dependent and independent androgen receptor activities in prostate cancer, and is authored by Wen, Niu, and Huang. This review summarizes posttranslational modifications of AR protein including phosphorylation, acetylation, methylation, ubiquitination, and SUMOylation. This review discusses the impact of these post-translational modifications on AR protein stability,nuclear localization,and transcriptional activity of AR.This review also discusses how these post-translational modifications regulate AR activity in prostate cancer.

The third review is entitledAndrogen receptor co-regulation in prostate cancer, and is authored by Senapati, Kumari, and Heemers. This review discusses the myriad interactions between AR proteins and various ligands, DNA binding motifs, and associated proteins,including coregulators and other transcription factors. This review also discusses how these interactions can collaborate to induce genomic locus-specific expression of AR target genes, likely via AR allosteric effects. These allosteric effects may influence the efficacy of therapeutics designed to inhibit AR transcriptional activity.

The fourth review is entitledCoordinated AR and micro-RNA regulation in prostate cancer, and is authored by Eringyte, Zamarbide Losada, Powell, Bevan, and Fletcher. This review summarizes mechanisms of dynamic bi-directional cross-talk between microRNAs (miRs, which are small～22 nt non-coding RNAs) and the AR signaling axis in prostate cancer. These pathways have potential to function as prostate cancer biomarkers and therapeutic targets.

The fifth review is entitledRegulation of androgen receptor variants in prostate cancer, and is authored by Zhu and Luo. This review focuses on studies addressing how AR variants (AR-Vs) such as AR-V7 are regulated in prostate cancer by genomic and epigenomic features acquired during progression of the disease to castration-resistant prostate cancer.

The sixth review is entitledLipogenic effects of androgen signaling in normal and malignant prostate, and is authored by Mah, Nassar, Swinnen, and Butler. This review addresses the fundamental metabolic relationships that are distinctive in normal versus malignant prostate tissues, and the role of androgens and AR in the regulation of lipid metabolism at different stages of prostate tumorigenesis.

The seventh review is entitledTherapeutic targeting of the androgen receptor (AR) and AR variants in prostate cancer, and is authored by Narayanan. This review summarizes the AR-signaling pathway-targeted therapeutics currently used in prostate cancer and the approaches that could be used for future development of novel AR targeted drugs. The review also outlines the discovery of molecules that bind to domains other than the AR ligand binding domain and those that inhibit both the full length AR and AR-Vs including AR-V7.

The eighth and final review is entitledAndrogen receptor in bladder cancer: a promising therapeutic target, and is authored by Tripathi and Gupta. This review summarizes the pre-clinical and clinical evidence that support a role for AR signaling in urothelial carcinoma pathogenesis and progression. This review will also discuss the potential role of AR as a novel therapeutic target in urothelial carcinoma.

Finally, we would like to thank all the authors for their great contributions to this special issue ofAJU. We hope these contributions will provide the urologic research community with an excellent overview of the regulation and function of AR in normal physiology and pathology of the urogenital tract, especially the prostate and bladder.