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.

在去势抵抗性前列腺癌（CRPC）中经常观察到雄激素受体（AR）的选择性剪接。一种AR同工型，AR-V7剪接变体，是组成型活性转录因子，其缺乏配体结合结构域，因此是不可吸收的。AR-V7表达与对雄激素受体信号抑制剂（ARSi）的耐药性和不良的临床预后相关。AR-V7剪接变体的出现是由剪接体对AR pre-mRNA的选择性剪接驱动的，但是对机理的细节了解甚少。我们证明，剪接因子RBM39对于AR前mRNA的AR-V7剪接变体mRNA转录的选择性剪接至关重要，并且抗癌药物Indisulam通过降解RBM39降低了AR-V7 mRNA的水平。我们报告称，Indisulam有效降低了AR-V7体外和体内模型。