Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States.
Elife. 2020 Dec 23;9:e59073. 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 (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.
卵巢小细胞癌，高钙血症型（SCCOHT）是一种罕见且侵袭性的卵巢癌形式。SCCOHT 肿瘤中存在 BRG1（SWI/SNF 染色质重塑复合物的两个相互排斥的 ATPase 之一）的失活突变。为了研究 BRG1 缺失在 SCCOHT 肿瘤发生中的作用，我们在 +/- BRG1 重新表达的 SCCOHT 细胞系中进行了综合多组学分析。BRG1 的重新表达诱导了类似于上皮细胞的基因和蛋白质特征，并获得了与其他上皮起源的 TCGA 肿瘤相关的染色质可及性位点。获得的染色质可及性和 BRG1 募集位点强烈富集了 AP-1 家族成员的转录因子结合基序。此外，AP-1 基序在上调的上皮基因的启动子处富集。使用显性负 AP-1 细胞系，我们发现 AP-1 DNA 结合活性和 BRG1 的重新表达对于上皮基因的基因和蛋白质表达都是必需的。我们的研究表明，BRG1 的重新表达在 SCCOHT 细胞中驱动上皮样基因和蛋白质特征，这取决于 AP-1 活性。
