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.

Krystal A. Orlando, Amber K. Douglas, Aierken Abudu, Yemin Wang, Basile Tessier-Cloutier, Weiping Su, Alec Peters, Larry S. Sherman, Rayvon Moore, Vinh Nguyen, Gian Luca Negri, Shane Colborne, Gregg B. Morin, Friedrich Kommoss, Jessica D. Lang, William P.D. Hendricks, Elizabeth A. Raupach, Patrick Pirrotte, David G. Huntsman, Jeffrey M. TrentJoel S. Parker, Jesse R. Raab, Bernard E. Weissman

    Research output: Contribution to journalArticlepeer-review

    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.

    Original languageEnglish (US)
    Article numbere59073
    Pages (from-to)1-57
    Number of pages57
    JournaleLife
    Volume9
    DOIs
    StatePublished - Dec 2020

    ASJC Scopus subject areas

    • Neuroscience(all)
    • Immunology and Microbiology(all)
    • Biochemistry, Genetics and Molecular Biology(all)

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