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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
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813545/ https://www.ncbi.nlm.nih.gov/pubmed/33355532 http://dx.doi.org/10.7554/eLife.59073 |
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author | Orlando, Krystal Ann Douglas, Amber K Abudu, Aierken Wang, Yemin Tessier-Cloutier, Basile Su, Weiping Peters, Alec Sherman, Larry S Moore, Rayvon Nguyen, Vinh Negri, Gian Luca Colborne, Shane Morin, Gregg B Kommoss, Friedrich Lang, Jessica D Hendricks, William PD Raupach, Elizabeth A Pirrotte, Patrick Huntsman, David G Trent, Jeffrey M Parker, Joel S Raab, Jesse R Weissman, Bernard E |
author_facet | Orlando, Krystal Ann Douglas, Amber K Abudu, Aierken Wang, Yemin Tessier-Cloutier, Basile Su, Weiping Peters, Alec Sherman, Larry S Moore, Rayvon Nguyen, Vinh Negri, Gian Luca Colborne, Shane Morin, Gregg B Kommoss, Friedrich Lang, Jessica D Hendricks, William PD Raupach, Elizabeth A Pirrotte, Patrick Huntsman, David G Trent, Jeffrey M Parker, Joel S Raab, Jesse R Weissman, Bernard E |
author_sort | Orlando, Krystal Ann |
collection | PubMed |
description | 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 reexpression. BRG1 reexpression 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 reexpression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that BRG1 reexpression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity. |
format | Online Article Text |
id | pubmed-7813545 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-78135452021-01-21 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 Orlando, Krystal Ann Douglas, Amber K Abudu, Aierken Wang, Yemin Tessier-Cloutier, Basile Su, Weiping Peters, Alec Sherman, Larry S Moore, Rayvon Nguyen, Vinh Negri, Gian Luca Colborne, Shane Morin, Gregg B Kommoss, Friedrich Lang, Jessica D Hendricks, William PD Raupach, Elizabeth A Pirrotte, Patrick Huntsman, David G Trent, Jeffrey M Parker, Joel S Raab, Jesse R Weissman, Bernard E eLife Cancer Biology 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 reexpression. BRG1 reexpression 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 reexpression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that BRG1 reexpression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity. eLife Sciences Publications, Ltd 2020-12-23 /pmc/articles/PMC7813545/ /pubmed/33355532 http://dx.doi.org/10.7554/eLife.59073 Text en © 2020, Orlando et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Orlando, Krystal Ann Douglas, Amber K Abudu, Aierken Wang, Yemin Tessier-Cloutier, Basile Su, Weiping Peters, Alec Sherman, Larry S Moore, Rayvon Nguyen, Vinh Negri, Gian Luca Colborne, Shane Morin, Gregg B Kommoss, Friedrich Lang, Jessica D Hendricks, William PD Raupach, Elizabeth A Pirrotte, Patrick Huntsman, David G Trent, Jeffrey M Parker, Joel S Raab, Jesse R Weissman, Bernard E 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813545/ https://www.ncbi.nlm.nih.gov/pubmed/33355532 http://dx.doi.org/10.7554/eLife.59073 |
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