Alternative splicing regulation by the androgen receptor in prostate cancer cells
| Autor: | Cindy Weidmann, Étienne Audet-Walsh, Lucas Germain, Raghavendra Tejo Karthik Poluri, Jolyane Beaudette, Camille Lafront |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Endocrinology Diabetes and Metabolism Clinical Biochemistry Biology Biochemistry Transcriptome 03 medical and health sciences 0302 clinical medicine Endocrinology Cell Line Tumor Humans RNA-Seq Molecular Biology Gene Transcription factor Alternative splicing Prostatic Neoplasms Cell Biology Malate dehydrogenase 1 Cell biology Androgen receptor Alternative Splicing 030104 developmental biology Receptors Androgen 030220 oncology & carcinogenesis RNA splicing Androgens Molecular Medicine TSC2 |
| Zdroj: | The Journal of Steroid Biochemistry and Molecular Biology. 202:105710 |
| ISSN: | 0960-0760 |
| Popis: | 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 prostate-specific membrane antigen, encoded by FOLH1, and the malate dehydrogenase 1 (MDH1). Overall, our study presents a comprehensive analysis of the PCa cell transcriptome and its modulation by AR, revealing a significant enrichment of metabolic genes in this AR-dependent regulation of alternative splicing. |
| Databáze: | OpenAIRE |
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