Journal
ONCOGENE
Volume 25, Issue 3, Pages 470-479Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209068
Keywords
SWI/SNF complex; nonsmall cell lung carcinoma; NRSF; neuronal differentiation; histone deacetylation
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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.
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