Negative regulation of the androgen receptor gene through a primate specific androgen response element present in the 5' UTR

The androgen receptor (AR) is a widely expressed ligand activated transcription factor which mediates androgen signalling by binding to androgen response elements (AREs) in normal tissue and prostate cancer (PCa). Within tumours, the amount of AR plays a crucial role in determining cell growth, resistance to therapy and progression to fatal castrate recurrent PCa in which prostate cells become independent of exoteric androgen. Despite the pivotal role of AR in all stages of PCa development, the mechanisms governing AR expression remain poorly understood. In this work, we describe an active non-consensus androgen response element in the 5’UTR of the human AR gene. The ARE represses transcription upon binding of activated AR, and this down-regulation is relieved by disruption of the regulatory element through mutation. Also, multiple species comparison of the genomic region reveals that this ARE is specific to primates, leading to the conclusion that extreme care must be exercised when elucidating the operation of the human AR in PCa based upon rodent promoter studies.