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 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.
Highlights
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer affecting young women[1,2]
Using a dominant negative AP-1 cell line, we found that both AP-1 DNA binding activity and BRG1 re[44] expression are necessary for the gene and protein expression of epithelial genes
In order to understand the global consequences of BRG1 loss in SCCOHT, we performed multi-omic analyses in parallel for the SCCOHT cell line BIN67 +/- BRG1 re-expression (Figure 1a)
Summary
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer affecting young women (mean age 24 years old)[1,2]. Over 94% of SCCOHT tumors have mutations and concomitant protein loss of SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling 52 complex[3,4,5,6,7,8,9]. The SWI/SNF complex is involved in a variety of cellular processes, such as differentiation and cell cycle control and interacts with transcription factors 11–13, such as CMYC14,15 and AP-116. Sites of gained chromatin accessibility were highly enriched for transcription factor motifs from AP-1 family members and strongly recruited BRG1. While the current study supports previous reports of SWI/SNF and AP-1 associations, it establishes a new biological connection between AP-1 and BRG1 to drive an epithelial cell-like differentiation in SCCOHT cell lines
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