The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells.
The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells.
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DOI：
10.1016/j.bmc.2020.115712
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发表时间：
2020-08
影响因子：
3.5
通讯作者：
James E. Melnyk;V. Steri;Hao G Nguyen;B. Hann;F. Feng;K. Shokat
中科院分区：
文献类型：
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作者：
James E. Melnyk;V. Steri;Hao G Nguyen;B. Hann;F. Feng;K. Shokat
雄激素受体（AR）的选择性剪接经常在去势抵抗性前列腺癌（CRPC）中观察到。一种AR同种型，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，因此不可用药。AR-V7表达与雄激素受体信号传导抑制剂（ARSi）的耐药性和不良临床表现相关。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，然而其机制细节知之甚少。我们证明了剪接因子RBM 39对于从AR前mRNA选择性剪接AR-V7剪接变体mRNA转录物至关重要，并且抗癌药物indisulam通过降解RBM 39降低AR-V7 mRNA水平。我们报道了茚磺草胺在体外和活体模型中有效地降低了AR-V7。
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 inin vitroandin vivomodels.