The use of Long Terminal Repeats as Androgen-Responsive Enhancers in the PSA-Kallikrein Locus (#66)
The androgen receptor (AR) signalling pathway is a common therapeutic target for prostate cancer because it is critical for the survival of both hormone-responsive and castrate-resistant tumour cells. Most of the detailed understanding we have of AR transcriptional activation has been gained by studying classical target genes. For more than two decades, Kallikrein 3 (KLK3, Prostate-Specific Antigen, PSA) has been used as a prototypical AR target gene because it is highly androgen-responsive in prostate cancer cells. Three regions upstream of the KLK3 gene, including the distal enhancer, are known to contain consensus androgen responsive elements required for AR-mediated transcriptional activation. Here we show that KLK3 is one of a specific cluster of androgen-regulated genes at the centromeric end of the kallikrein locus with enhancers that evolved from the long terminal repeat (LTR40a) of an endogenous retrovirus. Ligand-dependent recruitment of the AR to individual LTR-derived enhancers results in concurrent up-regulation of endogenous KLK2, KLK3, and KLKP1 expression in LNCaP prostate cancer cells. At the molecular level, a kallikrein-specific duplication within the LTR is required for maximal androgen responsiveness. Therefore, KLK3 represents a subset of target genes regulated by repetitive elements, but is not typical of the whole spectrum of androgen-responsive transcripts. These data provide a novel and more detailed understanding of AR transcriptional activation and emphasise the importance of repetitive elements as functional regulatory units.