SWI SNF complex is essential for NRSF-mediated suppression of neuronal genes in human nonsmall cell lung carcinoma cell lines

• Published in: Oncogene Vol. 25; no. 3; pp. 470 - 479
• Main Authors: WATANABE, H, MIZUTANI, T, HARAGUCHI, T, YAMAMICHI, N, MINOGUCHI, S, YAMAMICHI-NISHINA, M, MORI, N, KAMEDA, T, SUGIYAMA, T, IBA, H
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 19.01.2006; Nature Publishing Group
• Subjects: Base Sequence; Biological and medical sciences; Blotting, Western; Cancer; Carcinoma, Non-Small-Cell Lung - genetics; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; DNA Primers; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genes; Humans; Immunology; Immunoprecipitation; Lung Neoplasms - genetics; Medical sciences; Molecular and cellular biology; Neurons - metabolism; Neurosciences; Pneumology; Repressor Proteins - physiology; Reverse Transcriptase Polymerase Chain Reaction; Transcription factors; Transcription Factors - physiology; Tumors; Tumors of the respiratory system and mediastinum; Japan; Human; Lung disease; Respiratory disease; Suppression; Malignant tumor; Bronchopulmonary carcinoma; Carcinogenesis; Essential; neuronal differentiation; Cell line; Neuron; NRSF; Gene; Deacetylation; SWI/SNF complex; Bronchus disease; histone deacetylation; Differentiation; Histone; nonsmall cell lung carcinoma
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209068

Mammalian chromatin remodeling factor, 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.