A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer

Abstract

Persistent androgen receptor (AR) signalling is the main driver of prostate cancer (PCa). Truncated isoforms of the AR called androgen receptor variants (AR-Vs) lacking the ligand binding domain often emerge during treatment resistance against AR pathway inhibitors such as Enzalutamide. This review discusses how AR-Vs drive a more aggressive form of PCa through the regulation of some of their target genes involved in oncogenic pathways, enabling disease progression. There is a pressing need for the development of a new generation of AR inhibitors which can repress the activity of both the full-length AR and AR-Vs, for which the knowledge of differentially expressed target genes will allow evaluation of inhibition efficacy. This review provides a detailed account of the most common variant, AR-V7, the AR-V7 regulated genes which have been experimentally validated, endeavours to understand their relevance in aggressive AR-V driven PCa and discusses the utility of the downstream protein products as potential drug targets for PCa treatment.

Keywords: AR-V7; cancer; castration; gene; prostate.

Figure 1

Androgen Receptor signalling. A simplified schematic of Androgen Receptor (AR) Signalling: Full-Length Androgen Receptor, a transcription factor binds the testosterone derivative, Dihydrotestosterone (DHT) in the cytoplasm. The AR translocates to the nucleus, binds to Androgen Response Elements (AREs) on DNA and drives expression of cell survival and proliferation genes and target genes such as PSA (KLK3) and TMPRSS2 (2). NTD= amino-terminal domain, DBD= DNA-binding domain, LBD= Ligand-binding domain.

Figure 2

Structural representation of the Androgen Receptor and Androgen Receptor Variants. Full length Androgen Receptor (AR-FL) protein consists of three functional domains: an amino-terminal domain (NTD), DNA-binding domain (DBD) and Ligand-binding domain (LBD). Between the DBD and the LBD is a small hinge region (not shown). The AR gene resides on the X chromosome with 8 exons coding for the protein. Exon 1 codes for the N-terminal domain (NTD), exons 2 & 3 code for the DNA-binding domain (DBD) and exons 4-8 code for the hinge region (HR) and the ligand-binding domain (LBD). The NTD is the primary driver of AR-dependent transcription, the charged DBD allows interaction of AR with the DNA and the hydrophobic LBD facilitates androgen binding. Truncated AR variants (AR-Vs) lack the LBD (e.g. AR-V1 to AR-V14, inclusive of ARv567es) and instead, contain cryptic exons or partial LBD-coding exons or are non-functional and/or carry out alternate functions. In all cases these alterations diminish the ability of the AR to bind to ligands and subsequently be inhibited by LBD-targeting drugs such as Enzalutamide. CE, Cryptic Exon; EX, Exon; IN, Intron; p, Partial.

Figure 3

AR dimerisation and interaction with DNA. In AR-FL homodimers, the proteins intermolecularly associate by N/C interaction which is lost after DNA binding, allowing co-activator binding due to NTD and LBD separation. AR-FL/V7 heterodimers interact via N/C and D-Box interaction whereby the N/C interaction is also lost upon DNA binding. The AR-FL protein is immobilised on the DNA for a long time whereas AR-V7 protein demonstrates fast DNA-binding dynamics at high-affinity binding sites and dissociates from the dimer shortly after binding. AR-V7 homodimers have a short immobilisation time on the DNA, where dimers have close proximity via the DBD.

Figure 4

AR-V7 target genes promote Prostate Cancer progression by driving a more aggressive phenotype by activating multiple biological pathways.