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Molecular Cancer Research
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Cancer Genes and Networks

Loss of SWI/SNF Chromatin Remodeling Alters NRF2 Signaling in Non–Small Cell Lung Carcinoma

Shujie Song, Vinh Nguyen, Travis Schrank, Kathleen Mulvaney, Vonn Walter, Darmood Wei, Tess Orvis, Nisarg Desai, Jiren Zhang, D. Neil Hayes, Yanfang Zheng, Michael B. Major and Bernard E. Weissman
Shujie Song
1Oncology Center, ZhuJiang Hospital of Southern Medical University, Guangzhou, Guangdong, P. R. China.
2Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
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Vinh Nguyen
2Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
3Curriculum in Toxicology and Environmental Medicine, University of North Carolina, Chapel Hill, North Carolina.
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Travis Schrank
2Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
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Kathleen Mulvaney
2Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
4Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina.
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Vonn Walter
5Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania.
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Darmood Wei
3Curriculum in Toxicology and Environmental Medicine, University of North Carolina, Chapel Hill, North Carolina.
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Tess Orvis
2Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
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Nisarg Desai
2Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
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Jiren Zhang
1Oncology Center, ZhuJiang Hospital of Southern Medical University, Guangzhou, Guangdong, P. R. China.
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D. Neil Hayes
2Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
6Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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Yanfang Zheng
1Oncology Center, ZhuJiang Hospital of Southern Medical University, Guangzhou, Guangdong, P. R. China.
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  • For correspondence: weissman@med.unc.edu 18665000236@163.com bmajor@wustl.edu
Michael B. Major
2Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
4Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina.
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  • For correspondence: weissman@med.unc.edu 18665000236@163.com bmajor@wustl.edu
Bernard E. Weissman
2Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
3Curriculum in Toxicology and Environmental Medicine, University of North Carolina, Chapel Hill, North Carolina.
7Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.
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  • For correspondence: weissman@med.unc.edu 18665000236@163.com bmajor@wustl.edu
DOI: 10.1158/1541-7786.MCR-20-0082 Published December 2020
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Abstract

The NF-E2–related factor 2 (referred to as NRF2) transcription factor binds antioxidant responsive elements within the promoters of cytoprotective genes to induce their expression. Next-generation sequencing studies in lung cancer have shown a significant number of activating mutations within the NRF2 signaling pathway. Mutations in components of the SWI/SNF chromatin-remodeling complex, a general regulator of transcription using either BRG1 or BRM as the catalytic subunit, also frequently occur in lung cancers. Importantly, low BRG1 expression levels in primary human NSCLC correlated with increased NRF2-target gene expression. Here, we show that loss of SWI/SNF complex function activated a subset of NRF2-mediated transcriptional targets. Using a series of isogenic NSCLC lines with reduced or depleted BRG1 and/or BRM expression, we observed significantly increased expression of the NRF2-target genes HMOX1 and GSTM4. In contrast, expression of the NRF2 target genes NQO1 and GCLM modestly increased following BRM reduction. Chromatin immunoprecipitation showed that BRG1 knockdown led to increased NRF2 binding at its respective ARE sites in the HMOX1 promoter but not in NQO1 and GCLM. Our data demonstrate that loss of BRG1 or BRM in lung cancer results in activation of the NRF2/KEAP1 pathway and HMOX1 expression. Therefore, we provide an additional molecular explanation for why patients harboring BRG1 or BRM mutations show poor prognoses. A better understanding of this mechanism may yield novel insights into the design of targeted treatment modalities.

Implications: Our study identifies a novel mechanism for how mutations in the SMARCA4 gene may drive progression of human lung adenocarcinomas.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;18:1777–88

  • Received January 27, 2020.
  • Revision received January 30, 2020.
  • Accepted August 21, 2020.
  • Published first August 27, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 18 (12)
December 2020
Volume 18, Issue 12
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Loss of SWI/SNF Chromatin Remodeling Alters NRF2 Signaling in Non–Small Cell Lung Carcinoma
Shujie Song, Vinh Nguyen, Travis Schrank, Kathleen Mulvaney, Vonn Walter, Darmood Wei, Tess Orvis, Nisarg Desai, Jiren Zhang, D. Neil Hayes, Yanfang Zheng, Michael B. Major and Bernard E. Weissman
Mol Cancer Res December 1 2020 (18) (12) 1777-1788; DOI: 10.1158/1541-7786.MCR-20-0082

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Loss of SWI/SNF Chromatin Remodeling Alters NRF2 Signaling in Non–Small Cell Lung Carcinoma
Shujie Song, Vinh Nguyen, Travis Schrank, Kathleen Mulvaney, Vonn Walter, Darmood Wei, Tess Orvis, Nisarg Desai, Jiren Zhang, D. Neil Hayes, Yanfang Zheng, Michael B. Major and Bernard E. Weissman
Mol Cancer Res December 1 2020 (18) (12) 1777-1788; DOI: 10.1158/1541-7786.MCR-20-0082
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