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.
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).
The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity-independent genomic targetingNCBI Gene Expression Omnibus, GSE117735.
CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary (I)NCBI Gene Expression Omnibus, GSE120297.
Loss of SWI/SNF Chromatin Remodeling Alters NRF2 Signaling in Non-Small Cell Lung CarcinomaNCBI Gene Expression Omnibus, GSE162611.
- David G Huntsman
- Jeffrey M Trent
- Bernard E Weissman
- Joel S Parker
- Vinh Nguyen
- Jesse R Raab
- Larry S Sherman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Maureen E Murphy, The Wistar Institute, United States
© 2020, Orlando et al.
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