Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
Sci Rep. 2021 Jan 14;11(1):1393. doi: 10.1038/s41598-021-81164-0.
Prostate cancer (PCa) is dependent on the androgen receptor (AR). Advanced PCa is treated with an androgen deprivation therapy-based regimen; tumors develop resistance, although they typically remain AR-dependent. Expression of constitutively active AR variants lacking the ligand-binding domain including the variant AR-V7 contributes to this resistance. AR and AR-V7, as transcription factors, regulate many of the same genes, but also have unique activities. In this study, the capacity of the two AR isoforms to regulate splicing was examined. RNA-seq data from models that endogenously express AR and express AR-V7 in response to doxycycline were used. Both AR isoforms induced multiple changes in splicing and many changes were isoform-specific. Analyses of two endogenous genes, PGAP2 and TPD52, were performed to examine differential splicing. A novel exon that appears to be a novel transcription start site was preferentially induced by AR-V7 in PGAP2 although it is induced to a lesser extent by AR. The previously described AR induced promoter 2 usage that results in a novel protein derived from TPD52 (PrLZ) was not induced by AR-V7. AR, but not AR-V7, bound to a site proximal to promoter 2, and induction was found to depend on FOXA1.
前列腺癌 (PCa) 依赖于雄激素受体 (AR)。晚期 PCa 采用基于雄激素剥夺疗法的治疗方案；肿瘤产生耐药性，尽管它们通常仍然依赖于 AR。包括变体 AR-V7 在内的缺乏配体结合域的组成性激活 AR 变体的表达促成了这种耐药性。AR 和 AR-V7 作为转录因子，调节许多相同的基因，但也具有独特的活性。在这项研究中，检查了这两种 AR 亚型调节剪接的能力。使用内源性表达 AR 并响应多西环素表达 AR-V7 的模型的 RNA-seq 数据进行了分析。两种 AR 同种型都诱导了剪接的多种变化，许多变化是同种型特异性的。对两个内源性基因 PGAP2 和 TPD52 的分析，以检查差异剪接。在 PGAP2 中，一个似乎是新转录起始位点的新外显子主要由 AR-V7 诱导，尽管它被 AR 诱导的程度较小。先前描述的 AR 诱导的导致源自 TPD52 的新蛋白 (PrLZ) 的启动子 2 使用未被 AR-V7 诱导。AR，但不是 AR-V7，与靠近启动子 2 的位点结合，并且诱导被发现依赖于 FOXA1。
