Alternative splicing regulation by the androgen receptor in prostate cancer cells

The Journal of Steroid Biochemistry and Molecular Biology
Lucas GermainÉtienne Audet-Walsh

Abstract

The androgen receptor (AR) is a transcription factor that drives prostate cancer (PCa) by modulating the expression of thousands of genes to promote proliferation and survival and to reprogram metabolism. However, how AR activation controls alternative splicing is mostly unknown. Our objective was to define its role in the transcriptome-wide regulation of alternative splicing. Three human PCa models-LNCaP, LAPC4, and 22Rv1 cells-were treated with and without androgens, and RNA was purified for deep-sequencing analyses (RNA-seq). Several bioinformatic tools were then used to study alternative splicing. We demonstrate that in the absence of androgens, alternative splicing complexity is similar among AR-positive PCa cells, with 48 % of all transcripts having various levels of alternative splicing. We also describe alternative splicing differences among cell lines, such as specific splicing of AR, REST, TSC2, and CTBP1. Interestingly, AR activation changed the alternative splicing of thousands of genes in all the PCa cell lines tested. Overlap between AR-sensitive alternative splicing events revealed that genes linked to cell metabolism are major targets for this specific modulation. These genes encode metabolic enzymes such as the...Continue Reading

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