Androgen receptor enhancer usage and the chromatin regulatory landscape in human prostate cancers

Abstract

The androgen receptor (AR) is commonly known as a key transcription factor in prostate cancer development, progression and therapy resistance. Genome-wide chromatin association studies revealed that transcriptional regulation by AR mainly depends on binding to distal regulatory enhancer elements that control gene expression through chromatin looping to gene promoters. Changes in the chromatin epigenetic landscape and DNA sequence can locally alter AR-DNA-binding capacity and consequently impact transcriptional output and disease outcome. The vast majority of reports describing AR chromatin interactions have been limited to cell lines, identifying numerous other factors and interacting transcription factors that impact AR chromatin interactions. Do these factors also impact AR cistromics – the genome-wide chromatin-binding landscape of AR – in vivo? Recent technological advances now enable researchers to identify AR chromatin-binding sites and their target genes in human specimens. In this review, we provide an overview of the different factors that influence AR chromatin binding in prostate cancer specimens, which is complemented with knowledge from cell line studies. Finally, we discuss novel perspectives on studying AR cistromics in clinical samples.

Proteomic Landscape of Prostate Cancer: The View Provided by Quantitative Proteomics, Integrative Analyses, and Protein Interactomes

“…Significant differences exist in how strict analysis has been applied to the interaction confidence in the interpretation of potential interacting proteins. The interactome research relevant for prostate cancer is so far concentrated on AR and certain other transcription factors ( Figure 2 ), and is thus closely connected to events on chromatin (reviewed in [ 104 ]). In addition to target binding site sequences on DNA, protein–protein interactions play a large role in targeting transcription factors to sites on chromatin.…”

“…A subset of AR interactors was further investigated with chromatin immunoprecipitation assays. Interestingly, three major subgroups of genomic subcomplexes of AR interaction partners were identified, where FOXA1 and HOXB13, known transcription factors interacting with AR and affecting the AR cistrome in prostate cancer, dictate selective gain of function for AR action [ 104 ]. Launonen et al [ 113 ] utilized chromatin immunoprecipitation coupled with selective isolation of chromatin-associated proteins (ChIP-SICAP) to study the protein interaction network of chromatin-bound endogenous AR in VCaP cells in response to R1881.…”

Dysregulated Transcriptional Control in Prostate Cancer

“…This is controlled by multiple regulatory units mostly positioned within 50 kilobase-pairs of the gene they regulate, but in some cases also megabase-pairs away [16,17]. Long-range connections between distant regulatory elements are established by looping [18,19].…”

“…It is also a main driver of prostate cancer development due to reprogramming leading to a redistribution of AR binding sites and large transcriptome changes [90,157]. This is accompanied by a relocalization of FOXA1 and HOXB13 and the formation of novel genomic AR subcomplexes [19]. Importantly, transduction with these two pioneer transcription factors is sufficient for reprogramming normal prostate epithelium into transformed tumor cells [90].…”

Androgen-induced epigenetic modulations in the ovary

“…The dynamics between histone marks in the enhancer and/or promoter regions is mediated by regulating the expression and activity of various epigenetic enzymes (methylases/demethylases and/or acetylases/deacetylases) (Blum 2015, Hyun et al 2017. Androgens through both the extra-nuclear and nuclear pathways can repress/activate the expression and activity of epigenetic enzymes resulting in an increase or decrease of the histone marks affecting the expression of Figure 1 (A) Androgen-induced histone modifications occur in the distal enhancer and/or promoter regions of genes that in turn regulate gene expression (Stelloo et al 2019). (B) Mechanism of androgen-induced histone modifications: androgens through activation PI3K/Akt pathway and induction of miR-101 expression inhibit the enzymatic activity and expression of EZH2, a histone methyltransferase responsible for trimethylation of lysine 27 on histone 3 (H3K27me3), a gene repressive mark.…”