Cohesin mutations are synthetic lethal with stimulation of WNT signaling.
Cohesin mutations are synthetic lethal with stimulation of WNT signaling.
复制标题
粘着蛋白突变是合成的致命，并刺激Wnt信号传导。
DOI：
10.7554/elife.61405
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发表时间：
2020-12-07
期刊：
影响因子：
7.7
通讯作者：
Horsfield JA
中科院分区：
文献类型：
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作者：
Chin CV;Antony J;Ketharnathan S;Labudina A;Gimenez G;Parsons KM;He J;George AJ;Pallotta MM;Musio A;Braithwaite A;Guilford P;Hannan RD;Horsfield JA
编码内聚蛋白复合物亚基的基因突变在几种癌症中很常见，但也可能暴露出可药物治疗的脆弱性。我们产生了编码黏合蛋白亚基SMC3、RAD21和STAG2的基因缺失突变的等基因MCF10A细胞系，并用3009种fda批准的化合物筛选合成致死性。筛选发现了几种干扰转录、DNA损伤修复和细胞周期的化合物。出乎意料的是，最热门的药物之一是一种GSK3抑制剂，一种Wnt信号激动剂。我们发现，对GSK3抑制的敏感性可能是由于内聚蛋白突变细胞中β-连环蛋白的稳定，而wnt反应性基因表达在stag2突变的CMK白血病细胞中高度敏感。此外，Wnt在斑马鱼内聚蛋白亚基stag2b和rad21突变体中的活性增强。我们的研究结果表明，内聚蛋白突变可以通过增强Wnt信号通路来促进肿瘤的发生，并且靶向Wnt通路可能代表了一种治疗内聚蛋白突变癌症的新策略。
Mutations in genes encoding subunits of the cohesin complex are common in several cancers, but may also expose druggable vulnerabilities. We generated isogenic MCF10A cell lines with deletion mutations of genes encoding cohesin subunits SMC3, RAD21, and STAG2 and screened for synthetic lethality with 3009 FDA-approved compounds. The screen identified several compounds that interfere with transcription, DNA damage repair and the cell cycle. Unexpectedly, one of the top ‘hits’ was a GSK3 inhibitor, an agonist of Wnt signaling. We show that sensitivity to GSK3 inhibition is likely due to stabilization of β-catenin in cohesin-mutant cells, and that Wnt-responsive gene expression is highly sensitized in STAG2-mutant CMK leukemia cells. Moreover, Wnt activity is enhanced in zebrafish mutant for cohesin subunits stag2b and rad21. Our results suggest that cohesin mutations could progress oncogenesis by enhancing Wnt signaling, and that targeting the Wnt pathway may represent a novel therapeutic strategy for cohesin-mutant cancers.