Gene silencing associated with SWI/SNF complex loss during NSCLC development.
Gene silencing associated with SWI/SNF complex loss during NSCLC development.
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DOI：
10.1158/1541-7786.mcr-13-0427
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发表时间：
2014-04
期刊：
影响因子：
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通讯作者：
Weissman BE
中科院分区：
文献类型：
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作者：
Song S;Walter V;Karaca M;Li Y;Bartlett CS;Smiraglia DJ;Serber D;Sproul CD;Plass C;Zhang J;Hayes DN;Zheng Y;Weissman BE
SWI/SNF染色质重塑复合体以一种依赖于ATP的方式调节基因表达和改变染色质结构。最近的测序工作显示，BRG1(SMARCA4)是该复合体中两个相互排斥的ATPase亚基之一，在相当数量的人肺肿瘤细胞系和原发非小细胞肺癌(NSCLC)临床标本中发生突变。为了确定BRG1缺失如何促进NSCLC中的肿瘤进展，在BRG1缺失的NSCLC细胞中恢复BRG1表达或使用HDAC抑制剂或DNMT抑制剂处理后，进行了分子图谱分析。重要的是，来自多个细胞系的验证研究表明，BRG1的重新表达导致了CDH1、CDH3、EHF和RRAD的表达发生了实质性的变化，这些表达通常在NSCLC发育过程中经历了其他表观遗传机制的沉默。此外，用DNMT抑制剂处理不能恢复这些转录本的表达，这表明这种常见的基因沉默机制并不能解释它们的表达缺失。总之，BRG1缺失是非小细胞肺癌发育过程中靶基因表观遗传沉默的重要机制。
The SWI/SNF chromatin-remodeling complex regulates gene expression and alters chromatin structures in an ATP-dependent manner. Recent sequencing efforts have shown mutations in BRG1 (SMARCA4), one of two mutually exclusive ATPase subunits in the complex, in a significant number of human lung tumor cell lines and primary non-small cell lung carcinoma (NSCLC) clinical specimens. To determine how BRG1 loss fuels tumor progression in NSCLC, molecular profiling was performed after restoration of BRG1 expression or treatment with an HDAC inhibitor or a DNMT inhibitor in a BRG1-deficient NSCLC cells. Importantly, validation studies from multiple cell lines revealed that BRG1 re-expression led to substantial changes in the expression of CDH1, CDH3, EHF and RRAD that commonly undergo silencing by other epigenetic mechanisms during NSCLC development. Furthermore, treatment with DNMT inhibitors did not restore expression of these transcripts indicating that this common mechanism of gene silencing did not account for their loss of expression. Collectively, BRG1 loss is an important mechanism for the epigenetic silencing of target genes during NSCLC development.