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.

雄激素受体（AR）是一种转录因子，可通过调节成千上万个基因的表达来促进前列腺癌（PCa）的表达，从而促进增殖和存活并重新编程新陈代谢。但是，AR激活如何控制替代剪接尚不清楚。我们的目标是确定其在替代剪接的转录组范围内调控中的作用。使用和不使用雄激素对三种人类PCa模型（LNCaP，LAPC4和22Rv1细胞）进行了处理，并纯化了RNA用于深度测序分析（RNA-seq）。然后使用几种生物信息学工具来研究替代剪接。我们证明，在没有雄激素的情况下，AR阳性PCa细胞之间的可变剪接复杂度相似，所有转录本中有48％具有不同水平的可变剪接。AR，REST，TSC2和CTBP1。有趣的是，AR激活改变了所有测试的PCa细胞系中数千个基因的选择性剪接。AR敏感的选择性剪接事件之间的重叠表明，与细胞代谢相关的基因是这种特定调节的主要靶标。这些基因编码代谢酶，例如由FOLH1编码的前列腺特异性膜抗原和苹果酸脱氢酶1（MDH1）。总的来说，我们的研究提出了PCa细胞转录组及其受AR调控的综合分析，揭示了这种依赖于AR的可变剪接调控中代谢基因的大量富集。