THE EPIGENETIC CONSEQUENCES OF BRG1/SMARCA4 LOSS IN SMALL CELL CARCINOMA OF THE OVARY, HYPERCALCEMIC TYPE (SCCOHT) TUMORIGENESIS

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  • Orlando, Krystal Ann
    • School of Medicine, Department of Pathology and Laboratory Medicine
Abstract
  • Approximately 20% of all cancers have at least one or more mutations in the subunits of the SWI/SNF chromatin remodeling complex. Mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex, occur in >95% of small cell carcinomas of the ovary, hypercalcemic type (SCCOHT), a rare and aggressive form of ovarian cancer that occurs in young women. Because of its apparent role as a driver for SCCOHT, we performed integrative multi-omic analyses in a SCCOHT cell line +/- BRG1 re-expression to identify its role in SCCOHT tumorigenesis. After re-expression, BRG1 was recruited to both distal and promoter regions. We also observed increased chromatin accessibility at distal sites enriched for transcription factor binding motifs for AP-1 family members. Of interest, BRG1 re-expression induced an epithelial-like gene and protein expression concomitant with enrichment of AP-1 motifs at the TSS of highly upregulated epithelial genes. To determine the biological relevance of these changes at AP-1 binding sites, we used a dominant negative AP-1 cell line to demonstrate the necessity of AP-1 DNA binding activity and BRG1 re-expression for the protein expression of epithelial genes. Our study demonstrates that BRG1 loss may drive SCCOHT tumorigenesis by diminishing an epithelial-like gene and protein signature of its cell of origin driven by altered AP-1 binding.
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Advisor
  • Weissman, Bernard E
  • Parker, Joel S
  • Vaziri, Cyrus
  • Williams, David
  • Bultman, Scott
  • O'Connor, Siobhan
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2020
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