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

• Published in: eLife Vol. 9
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 23.12.2020; eLife Sciences Publications, Ltd; eLife Sciences Publications Ltd
• Subjects: Adenosine triphosphatase; Analysis; AP-1; Biomarkers, Tumor - analysis; BRG1; Cancer; Cancer Biology; Carcinoma; Carcinoma, Small Cell - genetics; Carcinoma, Small Cell - pathology; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Chromatin; DNA Helicases - genetics; DNA Helicases - metabolism; Epithelial; Female; Genes; Genetic aspects; Genetic research; Humans; Hypercalcemia - genetics; Hypercalcemia - pathology; multi-omics; Mutation - genetics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Ovarian cancer; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Ovary - metabolism; Ovary - pathology; SCCOHT; SWI/SNF; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; BRG1; SWI/SNF; multi-omics; SCCOHT; cancer biology; AP-1; human; Epithelial
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.59073

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.