Prostate cancer (PCa) is one of the most commonly diagnosed forms of cancer with one out of every nine North American men developing the disease in their lifetime. Despite robust early detection methods, new therapeutics, and advancements in surgical operations, PCa is still second leading cause of cancer death in men. An increasing number of studies have shown that non-coding mutations plays a critical role in the development and progression of PCa. These somatic mutations can disrupt regulatory elements such as enhancers and alter the transcriptional landscape of the cancer. Discovering and interpreting the non-coding elements is crucial to understand the nature of this disease.
At all stages of PCa, androgen receptor (AR) signaling is essential to the cancer. Recent work from our laboratory demonstrated that there is a significant increase in somatic mutations at AR binding sites (ARBS). Given the importance of AR-mediated transcription, as well as the recurrent nature of these mutations, we proposed that these somatic mutations could play an important role in PCa development. To stratify the mutations, we conducted a massively multi-parallel enhancer assay to identify those ARBS sites with enhancer activity. With STARR-seq we found that 8% of the ARBS had strong inducible AR enhancer activity (341/4139). Interestingly, the majority of these sites did not contain a canonical androgen response element. With these results we incorporated high-throughput chromosome conformation capture (HiC) to formally define the genes regulated by each of these AR enhancers. Based on these results we have selected and characterized several non-coding ARBS mutations. We believe that the importance of the regulatory role of these regions will play a tremendous role in understanding of the prostate cancer and its progression.
Citation Format: Dogancan Ozturan, Flora Huang, Tunc Morova, Mohammadali Saffarzadeh, Nathan A. Lack. Genome-wide AR enhancer activity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5208.