SNF5/INI1 deficiency redefines chromatin remodeling complex composition during tumor development.
SNF5/INI1 deficiency redefines chromatin remodeling complex composition during tumor development.
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DOI：
10.1158/1541-7786.mcr-14-0005
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发表时间：
2014-11
期刊：
影响因子：
--
通讯作者：
Kuwahara Y
中科院分区：
文献类型：
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作者：
Wei D;Goldfarb D;Song S;Cannon C;Yan F;Sakellariou-Thompson D;Emanuele M;Major MB;Weissman BE;Kuwahara Y
恶性横纹肌样瘤（MRT）是一种最常出现在肾脏和大脑中的儿科癌症，通常缺乏SNF 5（SMARCB 1/INI 1），这是SWI/SNF染色质重塑复合物的一个亚基。最近的研究已经确定，由于存在或不存在不同的复合物成员，存在多个SWI/SNF复合物。因此，在人MRT细胞中研究了SNF 5损失对SWI/SNF复合物形成的影响。MRT细胞和原发性人类肿瘤表现出许多复杂蛋白质的水平降低。此外，SNF 5的再表达增加了SWI/SNF复合物蛋白水平，而没有伴随mRNA的增加。蛋白质组学分析，使用质谱，MRT细胞之前和之后SNF 5的重新表达表明，不同的组成部分的招聘到复杂的沿着与其他驱逐。IP-Western印迹证实了这些结果，并在其他MRT细胞系中表现出类似的变化。最后，正常人成纤维细胞中SNF 5表达的减少导致这些相同复合物成员的水平改变。这些数据表明，SNF 5在MRT发展过程中的损失改变了可用的SWI/SNF复合物的库，通常破坏了与细胞分化相关的那些。这些发现支持SNF 5失活阻断生长促进SWI/SNF复合物向分化诱导复合物转化的模型。因此，在肿瘤细胞中恢复这些复合物为治疗恶性横纹肌样肿瘤提供了一种有吸引力的方法。SNF 5的丢失显著改变了SWI/SNF复合物的组成，并阻止了细胞分化所需的复合物的形成。
Malignant Rhabdoid Tumors (MRTs), a pediatric cancer that most frequently appears in the kidney and brain, generally lack SNF5 (SMARCB1/INI1), a subunit of the SWI/SNF chromatin-remodeling complex. Recent studies have established that multiple SWI/SNF complexes exist due to the presence or absence of different complex members. Therefore, the effect of SNF5 loss upon SWI/SNF complex formation was investigated in human MRT cells. MRT cells and primary human tumors exhibited reduced levels of many complex proteins. Furthermore, re-expression of SNF5 increased SWI/SNF complex protein levels without concomitant increases in mRNA. Proteomic analysis, using mass spectrometry, of MRT cells before and after SNF5 re-expression indicated the recruitment of different components into the complex along with the expulsion of others. IP-Western blotting confirmed these results and demonstrated similar changes in other MRT cell lines. Finally, reduced expression of SNF5 in normal human fibroblasts led to altered levels of these same complex members. These data establish that SNF5 loss during MRT development alters the repertoire of available SWI/SNF complexes, generally disrupting those associated with cellular differentiation. These findings support a model where SNF5 inactivation blocks the conversion of growth promoting SWI/SNF complexes to differentiation inducing ones. Therefore, restoration of these complexes in tumors cells provides an attractive approach for the treatment of malignant rhabdoid tumors. SNF5 loss dramatically alters SWI/SNF complex composition and prevents formation of complexes required for cellular differentiation.