SWI/SNF complex is essential for NRSF-mediated suppression of neuronal genes in human nonsmall cell lung carcinoma cell lines
SWI/SNF complex is essential for NRSF-mediated suppression of neuronal genes in human nonsmall cell lung carcinoma cell lines
复制标题
DOI：
10.1038/sj.onc.1209068
复制
发表时间：
2006-01-01
期刊：
影响因子：
8
通讯作者：
Iba, H
中科院分区：
文献类型：
--
作者：
Watanabe, H;Mizutani, T;Iba, H
哺乳动物染色质重构因子或SWI/ SNF复合物含有作为ATP酶催化亚基的Brm或BRG 1的单个分子。在这里，我们表明，SWI/ SNF复合物形成了一个更大的复杂的神经元限制性沉默因子（NRSF）和它的辅阻遏物，mSin 3A和CoREST，在人类非小细胞肺癌细胞系。我们还证明了NRSF在这些非神经细胞中对突触素和SCG 10等神经元特异性基因的强烈转录抑制需要功能性SWI/ SNF复合物;这些神经元基因在缺乏Brm和BRG 1的细胞系中升高，而表达靶向SWI/ SNF复合物的组成部分的siRNA的逆转录病毒载体（Brm/BRG 1或BRM 1）在SWI/SNF感受态细胞系中诱导这些神经元基因的表达。在Brm和BRG 1均缺陷的细胞系中，外源Brm或BRG 1以ATP依赖性方式抑制这些神经元基因的表达，并通过包含募集功能性SWI/ SNF复合物的大复合物诱导突触素基因中存在的NRSF结合位点周围的组蛋白H4高效且特异性的脱乙酰化。据报道，Brm/BRG 1缺陷型肺癌患者预后不良; NRSF调控基因（包括这些神经元特异性基因）的去抑制可能有助于增强致瘤性，也将为Brm/BRG 1缺陷型肿瘤提供选择性标记。
Mammalian chromatin remodelingfact or, SWI/ SNF complex contains a single molecule of either Brm or BRG1 as the ATPase catalytic subunit. Here, we show that the SWI/ SNF complex forms a larger complex with neuron-restrictive silencer factor (NRSF) and its corepressors, mSin3A and CoREST, in human nonsmall cell lung carcinoma cell lines. We also demonstrate that the strong transcriptional suppression of such neuron-specific genes as synaptophysin and SCG10 by NRSF in these non-neural cells requires the functional SWI/ SNF complex; these neuronal genes were elevated in cell lines deficient in both Brm and BRG1, whereas retrovirus vectors expressing siRNAs targeting integral components of SWI/ SNF complex (Brm/BRG1 or Ini1) induced expression of these neuronal genes in SWI/ SNF-competent cell lines. In cell lines deficient in both Brm and BRG1, exogenous Brm or BRG1 suppressed expression of these neuronal genes in an ATP-dependent manner and induced efficient and specific deacetylation of histone H4 around the NRSF binding site present in the synaptophysin gene by a large complex containing the recruited functional SWI/ SNF complex. Patients with Brm/BRG1 deficient lung carcinoma have been reported to carry poor prognosis; derepression of NRSF-regulated genes including these neuron-specific genes could contribute to enhance tumorigenicity and also would provide selective markers for Brm/BRG1-deficient tumors.