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 appear to become independent of androgenic steroids. Despite the pivotal role of the AR in male development and fertility and all stages of PCa development, the mechanisms governing AR expression remain poorly understood. In this work, we describe an active nonconsensus androgen response element (ARE) in the 5′ UTR of the human AR gene. The ARE represses transcription upon binding of activated AR, and this downregulation 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 care must be exercised when elucidating the operation of the human AR in PCa based upon rodent promoter studies.