Gene silencing associated with SWI/SNF complex loss during NSCLC development.
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 a histone deacetylase inhibitor or a DNA methyltransferase (DNMT) inhibitor in a BRG1-deficient NSCLC cells. Importantly, validation studies from multiple cell lines revealed that BRG1 reexpression 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.


CONCLUSIONS
Inactivation of the SWI/SNF complex provides a novel mechanism to induce gene silencing during NSCLC development.
Lineberger Cancer Center, Room 32-048, University of North Carolina, Chapel Hill, NC 27599-7295. weissman@med.unc.edu.
Shujie
S
Song
Vonn
V
Walter
Mehmet
M
Karaca
Ying
Y
Li
Christopher S
CS
Bartlett
Dominic J
DJ
Smiraglia
Daniel
D
Serber
Christopher D
CD
Sproul
Christoph
C
Plass
Jiren
J
Zhang
D Neil
DN
Hayes
Yanfang
Y
Zheng
Bernard E
BE
Weissman
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency* / Q000235:genetics; D004265:DNA Helicases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D019175:DNA Methylation; D018450:Disease Progression; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D011401:Promoter Regions, Genetic; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D014162:Transfection
D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases