title: BRG1/SMARCA4 inactivation promotes non-small cell lung cancer aggressiveness by altering chromatin organization.
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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.
authors.forename: Tess
authors.initials: T
authors.lastname: Orvis
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.|Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Hepperla
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.
authors.forename: Vonn
authors.initials: V
authors.lastname: Walter
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.|Cancer Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China.
authors.forename: Shujie
authors.initials: S
authors.lastname: Song
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.|Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Simon
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.|Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Parker
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.|Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wilkerson
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.
authors.forename: Nisarg
authors.initials: N
authors.lastname: Desai
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.|Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Major
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.|Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.|Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.|Department of Pediatrics and Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Davis
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.|Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Weissman
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000502:physiology*; D004265:DNA Helicases / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D009707:Nucleosomes; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D002843:Chromatin; C112442:Ehf protein, mouse; D009687:Nuclear Proteins; D009707:Nucleosomes; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases