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Alternative RNA splicing of the androgen receptor gene in prostate cancer

Xuesen Dong, MD, MSc, PhD, University of British Columbia, Vancouver Prostate Centre

It is widely accepted that AR becomes more sensitive to its ligands and remains ligand-activated in castration-resistant prostate cancers. This concept directs the research to design stronger AR antagonists or androgen synthesis inhibitors, to achieve better outcomes for cancer  patients. However, we identified a novel AR splice variant, ARv567es, which constitutively actives AR targeted genes without androgen binding. It is produced by alternative RNA splicing that skips the 3’ splice site of intron 4 of AR pre-mRNA, resulting exon 5-7 deletion in mature AR mRNA. Castration induces ARv567es levels. ARv567es bearing tumors progress despite of castration. Therefore, developing therapeutic strategies for castration-resistant cancers should consider blocking ARv567es formation, which requires understanding of AR alternative splicing program. We recognize there are several AR variants with similar functions. However, we chose ARv567es because it occurs with a high frequency in clinical tumors and is the only variant that is clearly regulated by tumor androgen levels.

Alternative splicing is primarily processed by SR and hnRNP splicing factors. Once recruited, they determine a splice site to be excised. We hypothesize that castration changes SR/hnRNP recruitment to the 3’ splice site of intron 4 leading to ARv567es formation. We propose to apply RNA binding and CHIP techniques to 1) define SR/hnRNP recruitment to the 3’ splice site in pre- and post-castration conditions, and 2) compare the recruitments of SR/hnRNP proteins to the 3’ splice site between ARv567es positive and negative tumors. Information obtained from these studies would lead to novel treatments for castration-resistant prostate cancers.

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