Targeting WDR5: A WINning Anti-Cancer Strategy?
Targeting WDR5: A WINning Anti-Cancer Strategy?
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DOI：
10.1177/2516865719865282
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发表时间：
2019-07-18
影响因子：
2.2
通讯作者：
Tansey, William P.
中科院分区：
文献类型：
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作者：
Aho, Erin R.;Weissmiller, April M.;Tansey, William P.
WDR 5是多种表观遗传调控复合物的组分，包括存款组蛋白H3赖氨酸4甲基化的混合谱系白血病（MLL）/SET复合物。WDR 5中的精氨酸结合腔的抑制剂，称为WDR 5-相互作用（WIN）位点，已经提出通过表观遗传机制选择性地杀死MLL重排的恶性肿瘤。我们发现了有效的WIN位点抑制剂，并发现它们不是通过组蛋白甲基化的变化杀死MLL癌细胞。而是通过在蛋白质合成基因处将WDR 5从染色质中置换出来，窒息这些细胞的翻译能力，并通过核仁应激反应诱导死亡。WIN位点抑制剂的作用机制揭示了WDR 5功能的新方面，并预测了作为抗癌剂的广泛治疗用途。
WDR5 is a component of multiple epigenetic regulatory complexes, including the mixed lineage leukemia (MLL)/SET complexes that deposit histone H3 lysine 4 methylation. Inhibitors of an arginine-binding cavity in WDR5, known as the WDR5-interaction (WIN) site, have been proposed to selectively kill MLL-rearranged malignancies via an epigenetic mechanism. We discovered potent WIN site inhibitors and found that they kill MLL cancer cells not through changes in histone methylation. but by displacing WDR5 from chromatin at protein synthesis genes, choking the translational capacity of these cells, and inducing death via a nucleolar stress response. The mechanism of action of WIN site inhibitors reveals new aspects of WDR5 function and forecasts broad therapeutic utility as anti-cancer agents.