Androgen receptor-driven chromatin looping in prostate cancer

Abstract

The androgen receptor (AR) is important for prostate cancer development and progression. Genome-wide mapping of AR binding sites in prostate cancer has found that the majority of AR binding sites are located within non-promoter regions. These distal AR binding regions regulate AR target genes (e.g. UBE2C) involved in prostate cancer growth through chromatin looping. In addition to long-distance gene regulation, looping has been shown to induce spatial proximity of two genes otherwise located far away along the genomic sequence and the formation of double-strand DNA breaks, resulting in aberrant gene fusions (e.g. TMPRSS2-ERG) that also contribute to prostate tumorigenesis. Elucidating the mechanisms of AR-driven chromatin looping will increase our understanding of prostate carcinogenesis and may lead to the identification of new therapeutic targets.

Figure 1

A proposed looping model for AR-regulated gene expression in CRPC. Active histone modifications (e.g. H3K4me1 and H3K4me2) facilitate the binding of AR and its collaborating transcription factors (e.g. FoxA1) to distal nucleosome-depleted regions^, . p-MED1 mediates chromatin looping by facilitating interactions between distal transcription factors and the basal transcriptional apparatus^, . Other coactivators (e.g. p160 coactivators and p300) may also enhance chromatin looping. Cohension may stabilize chromatin looping by embracing the loop. AR, androgen receptor; H3K4me1 and H3K4me2, H3K4 mono- and di-methylation; p-MED1, PI3K/AKT phosphorylated MED1.

Figure 2

AR-mediated TMPRSS2-ERG gene fusion in prostate cancer cells. (A) In the presence of genotoxic stress, AR binds to TMPRSS2 and ERG breakpoints and recruits AID upon DHT treatment. Exposure of prostate cancer cells under genotoxic stress to DHT also increases ORF2 recruitment to breakpoints. DHT stimulation only leads to AR-TOP2B complex loading on breakpoints. (B) The recruitment of AID, ORF2 and TOP2B to breakpoints causes DSB^, . (C) NHEJ machinery is recruited to the breakpoints, leading to error-prone DSB repair and gene fusions such as TMPRSS2-ERG gene fusion^, . AID, activation-induced cytidine deaminase; DHT, dihydrotestosterone; ORF2, open reading frame 2; TOP2B, topoimerase II beta; NHEJ, non-homologous end joining.