Re-expression of SMARCA4/BRG1 in Small Cell Carcinoma of Ovary, Hypercalcemic Type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism
- University of North Carolina at Chapel Hill, United States
- Michigan State University, United States
- University of British Columnia, Canada
- Oregon Health & Science University, United States
- British Columbia Cancer Agency, Canada
- Synlab MVZ Pathologie, Germany
- Translational Genomics Research Institute, United States
- British Columbia Cancer Research Institute, Canada
Abstract
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in SCCOHT cell lines +/- BRG1 re-expression. BRG1 re-expression induced a gene and protein signature similar to an epithelial cell and gained chromatin accessibility sites correlated with other epithelial originating TCGA tumors. Gained chromatin accessibility and BRG1 recruited sites were strongly enriched for transcription factor binding motifs of AP-1 family members. Furthermore, AP-1 motifs were enriched at the promoters of highly upregulated epithelial genes. Using a dominant negative AP-1 cell line, we found that both AP-1 DNA binding activity and BRG1 re-expression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that BRG1 re-expression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity.
Data availability
Raw fastq files and processed data have been deposited in Gene Expression Omnibus (GEO) database with the accession number: GSE151026. Proteomics data was deposited in PRIDE database (accession #PXD014134).
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Loss of SWI/SNF Chromatin Remodeling Alters NRF2 Signaling in Non-Small Cell Lung CarcinomaNCBI Gene Expression Omnibus, GSE162611.
Article and author information
Author details
Bernard E Weissman
Funding
National Institutes of Health (R01CA195670)
- David G Huntsman
- Jeffrey M Trent
- Bernard E Weissman
National Institutes of Health (P30CA016086)
- Joel S Parker
National Institutes of Health (T32ES007126)
- Vinh Nguyen
Department of Defense (W81XWH-19-1-0423)
- Jesse R Raab
National Institutes of Health (P51 OD 011092)
- Larry S Sherman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Maureen E Murphy, The Wistar Institute, United States
Version history
- Received: May 19, 2020
- Accepted: December 22, 2020
- Accepted Manuscript published: December 23, 2020 (version 1)
- Version of Record published: January 18, 2021 (version 2)
Copyright
© 2020, Orlando et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Re-expression of SMARCA4/BRG1 in Small Cell Carcinoma of Ovary, Hypercalcemic Type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism
eLife 9:e59073.
https://doi.org/10.7554/eLife.59073
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