Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Preclinical Therapeutics Core, University of California San Francisco, San Francisco, CA 94158, USA.
Bioorg Med Chem. 2020 Oct 15;28(20):115712. doi: 10.1016/j.bmc.2020.115712. Epub 2020 Aug 18.
Alternative splicing of the androgen receptor (AR) is frequently observed in castration resistant prostate cancer (CRPC). One AR isoform, the AR-V7 splice variant, is a constitutively active transcription factor which lacks a ligand binding domain and is therefore undruggable. AR-V7 expression correlates with resistance to androgen receptor signaling inhibitors (ARSi) and poor clinical prognoses. The occurrence of the AR-V7 splice variant is driven by alternative splicing of AR pre-mRNA by the spliceosome, however the mechanistic details are poorly understood. We demonstrate that the splicing factor RBM39 is critical for alternative splicing of the AR-V7 splice variant mRNA transcripts from AR pre-mRNA, and that the anti-cancer drug, indisulam, reduces AR-V7 mRNA levels by degrading RBM39. We report that indisulam effectively reduces AR-V7 in in vitro and in vivo models.
雄激素受体 (AR) 的选择性剪接在去势抵抗性前列腺癌 (CRPC) 中经常观察到。AR 的一种异构体，即 AR-V7 剪接变异体，是一种组成型激活的转录因子，缺乏配体结合域，因此无法用药物治疗。AR-V7 的表达与雄激素受体信号抑制剂 (ARSi) 的耐药性和不良临床预后相关。AR-V7 剪接变体的发生是由剪接体对 AR 前体 mRNA 的选择性剪接驱动的，但机制细节知之甚少。我们证明，剪接因子 RBM39 对于 AR 前体 mRNA 中 AR-V7 剪接变体 mRNA 转录物的选择性剪接至关重要，并且抗癌药物 indisulam 通过降解 RBM39 降低 AR-V7 mRNA 水平。我们报告说，indisulam 在体外和体内模型中有效地降低了 AR-V7。
