BRG1/SMARCA4 Inactivation Promotes Non–Small Cell Lung Cancer Aggressiveness by Altering Chromatin Organization
- 13 November 2014
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 74 (22), 6486-6498
- https://doi.org/10.1158/0008-5472.can-14-0061
Abstract
SWI/SNF chromatin remodeling complexes regulate critical cellular processes, including cell-cycle control, programmed cell death, differentiation, genomic instability, and DNA repair. Inactivation of this class of chromatin remodeling complex has been associated with a variety of malignancies, including lung, ovarian, renal, liver, and pediatric cancers. In particular, approximately 10% of primary human lung non–small cell lung cancers (NSCLC) display attenuations in the BRG1 ATPase, a core factor in SWI/SNF complexes. To evaluate the role of BRG1 attenuation in NSCLC development, we examined the effect of BRG1 silencing in primary and established human NSCLC cells. BRG1 loss altered cellular morphology and increased tumorigenic potential. Gene expression analyses showed reduced expression of genes known to be associated with progression of human NSCLC. We demonstrated that BRG1 losses in NSCLC cells were associated with variations in chromatin structure, including differences in nucleosome positioning and occupancy surrounding transcriptional start sites of disease-relevant genes. Our results offer direct evidence that BRG1 attenuation contributes to NSCLC aggressiveness by altering nucleosome positioning at a wide range of genes, including key cancer-associated genes. Cancer Res; 74(22); 6486–98. ©2014 AACR.Keywords
Other Versions
This publication has 64 references indexed in Scilit:
- Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancyNature Genetics, 2013
- Comprehensive genomic characterization of squamous cell lung cancersNature, 2012
- Regulation of nucleosome landscape and transcription factor targeting at tissue-specific enhancers by BRG1Genome Research, 2011
- High nucleosome occupancy is encoded at X-linked gene promoters in C. elegansGenome Research, 2010
- MapSplice: Accurate mapping of RNA-seq reads for splice junction discoveryNucleic Acids Research, 2010
- Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cellsCarcinogenesis: Integrative Cancer Research, 2010
- The Sequence Alignment/Map format and SAMtoolsBioinformatics, 2009
- Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell linesHuman Mutation, 2008
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- Significance analysis of microarrays applied to the ionizing radiation responseProceedings of the National Academy of Sciences of the United States of America, 2001