BRG1/SMARCA4 inactivation promotes non-small cell lung cancer aggressiveness by altering chromatin organization

Tess Orvis, Austin Hepperla, Vonn Walter, Shujie Song, Jeremy Simon, Joel Parker, Matthew D. Wilkerson, Nisarg Desai, Michael B. Major, D. Neil Hayes, Ian J. Davis, Bernard Weissman

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6486-6498
Number of pages13
JournalCancer Research
Volume74
Issue number22
DOIs
StatePublished - Nov 15 2014

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Non-Small Cell Lung Carcinoma
Chromatin
Chromatin Assembly and Disassembly
Nucleosomes
Gene Expression
Lung
Genomic Instability
Neoplasm Genes
Liver Neoplasms
Cell Cycle Checkpoints
DNA Repair
Genes
Adenosine Triphosphatases
Cell Differentiation
Cell Death
Pediatrics
Kidney
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Orvis, Tess ; Hepperla, Austin ; Walter, Vonn ; Song, Shujie ; Simon, Jeremy ; Parker, Joel ; Wilkerson, Matthew D. ; Desai, Nisarg ; Major, Michael B. ; Hayes, D. Neil ; Davis, Ian J. ; Weissman, Bernard. / BRG1/SMARCA4 inactivation promotes non-small cell lung cancer aggressiveness by altering chromatin organization. In: Cancer Research. 2014 ; Vol. 74, No. 22. pp. 6486-6498.
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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.",
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Orvis, T, Hepperla, A, Walter, V, Song, S, Simon, J, Parker, J, Wilkerson, MD, Desai, N, Major, MB, Hayes, DN, Davis, IJ & Weissman, B 2014, 'BRG1/SMARCA4 inactivation promotes non-small cell lung cancer aggressiveness by altering chromatin organization', Cancer Research, vol. 74, no. 22, pp. 6486-6498. https://doi.org/10.1158/0008-5472.CAN-14-0061

BRG1/SMARCA4 inactivation promotes non-small cell lung cancer aggressiveness by altering chromatin organization. / Orvis, Tess; Hepperla, Austin; Walter, Vonn; Song, Shujie; Simon, Jeremy; Parker, Joel; Wilkerson, Matthew D.; Desai, Nisarg; Major, Michael B.; Hayes, D. Neil; Davis, Ian J.; Weissman, Bernard.

In: Cancer Research, Vol. 74, No. 22, 15.11.2014, p. 6486-6498.

Research output: Contribution to journalArticle

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AU - Orvis, Tess

AU - Hepperla, Austin

AU - Walter, Vonn

AU - Song, Shujie

AU - Simon, Jeremy

AU - Parker, Joel

AU - Wilkerson, Matthew D.

AU - Desai, Nisarg

AU - Major, Michael B.

AU - Hayes, D. Neil

AU - Davis, Ian J.

AU - Weissman, Bernard

PY - 2014/11/15

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N2 - 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.

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