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The Interaction of SWI/SNF with the Ribosome Regulates Translation and Confers Sensitivity to Translation Pathway Inhibitors in Cancers with Complex Perturbations
Cancer Research ( IF 11.2 ) Pub Date : 2022-06-24 , DOI: 10.1158/0008-5472.can-21-1360
Livia Ulicna 1 , Samuel C Kimmey 1, 2 , Christopher M Weber 1 , Grace M Allard 1 , Aihui Wang 1 , Nam Q Bui 2 , Sean C Bendall 1 , Gerald R Crabtree 1, 3 , Gregory R Bean 1 , Capucine Van Rechem 1
Affiliation  

Subunits from the chromatin remodelers mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) are mutated, deleted, or amplified in more than 40% of cancers. Understanding their functions in normal cells and the consequences of cancerous alterations will provide insight into developing new targeted therapies. Here we examined whether mSWI/SNF mutations increase cellular sensitivity to specific drugs. Taking advantage of the DepMap studies, we demonstrate that cancer cells harboring mutations of specific mSWI/SNF subunits exhibit a genetic dependency on translation factors and are sensitive to translation pathway inhibitors. Furthermore, mSWI/SNF subunits were present in the cytoplasm and interacted with the translation initiation machinery, and short-term inhibition and depletion of specific subunits decreased global translation, implicating a direct role for these factors in translation. Depletion of specific mSWI/SNF subunits also increased sensitivity to mTOR-PI3K inhibitors. In patient-derived breast cancer samples, mSWI/SNF subunits expression in both the nucleus and the cytoplasm was substantially altered. In conclusion, an unexpected cytoplasmic role for mSWI/SNF complexes in translation suggests potential new therapeutic opportunities for patients afflicted by cancers demonstrating alterations in their subunits. Significance: This work establishes direct functions for mSWI/SNF in translation and demonstrates that alterations in mSWI/SNF confer a therapeutic vulnerability to translation pathway inhibitors in cancer cells.

中文翻译:

SWI/SNF 与核糖体的相互作用调节翻译并赋予具有复杂扰动的癌症中翻译途径抑制剂的敏感性

超过 40% 的癌症中,哺乳动物 SWIitch/蔗糖不可发酵 (mSWI/SNF) 染色质重塑亚基发生突变、缺失或扩增。了解它们在正常细胞中的功能以及癌症改变的后果将为开发新的靶向疗法提供见解。在这里,我们检查了 mSWI/SNF 突变是否会增加细胞对特定药物的敏感性。利用 DepMap 研究,我们证明携带特定 mSWI/SNF 亚基突变的癌细胞表现出对翻译因子的遗传依赖性,并且对翻译途径抑制剂敏感。此外,mSWI/SNF 亚基存在于细胞质中,并与翻译起始机制相互作用,特定亚基的短期抑制和耗尽会降低整体翻译,表明这些因素在翻译中发挥直接作用。特定 mSWI/SNF 亚基的消耗也增加了对 mTOR-PI3K 抑制剂的敏感性。在患者来源的乳腺癌样本中,细胞核和细胞质中的 mSWI/SNF 亚基表达发生了显着改变。总之,mSWI/SNF 复合物在翻译过程中意想不到的细胞质作用表明,对于亚基发生改变的癌症患者来说,有潜在的新治疗机会。意义:这项工作确立了 mSWI/SNF 在翻译中的直接功能,并证明 mSWI/SNF 的改变赋予癌细胞中翻译途径抑制剂的治疗脆弱性。
更新日期:2022-06-24
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