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Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) cell line H3K27ac CUT&RUN

ABSTRACT: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) cell line H3K27ac CUT&RUN

PROVIDER: PRJNA973644 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24622847_1.fastq.gz	Fastqsanger.gz
	SRR24622847_2.fastq.gz	Fastqsanger.gz
	SRR24622848_1.fastq.gz	Fastqsanger.gz
	SRR24622848_2.fastq.gz	Fastqsanger.gz
	SRR24622849_1.fastq.gz	Fastqsanger.gz

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Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) tumor gene expression

Project description:Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare form of ovarian cancer that has not previously been characterized at the gene expression level. The goal of this study was to generate gene expression profiles from SCCOHT tumor samples by RNA-Seq.

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Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) cell line H3K27ac CUT&RUN

Project description:Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare form of ovarian cancer affecting young women and girls. Survival rates remain poor despite aggressive treatment of these patients with high-dose chemotherapy and radiation. SCCOHT is driven by loss of both SWI/SNF ATPases SMARCA4 and SMARCA2. Loss of SWI/SNF complex activity alters chromatin state, particularly at enhancers, which is believed to be crucial for oncogenesis. Super-enhancers are a distinct subset of enhancer clusters frequently associated with oncogenes in cancer. Here we discovered key distinctions between SWI/SNF binding following SMARCA4 restoration at enhancer vs. super-enhancer sites and characterized putative oncogene expression driven by super-enhancer activity. We found high sensitivity of SCCOHT cell lines to triptolide, a small molecule derived from the naturally occurring "thunder god vine" (Tripterygium wilfordii) that targets the XPB subunit of the transcription factor II H (TFIIH) complex, found at super-enhancers. Triptolide inhibits expression of many super-enhancer associated genes, and in particular, oncogenes. Notably, SALL4 expression, which is high in SCCOHT relative to other ovarian cancers and normal cell types, is significantly decreased following short triptolide treatment. In SCCOHT patient-derived xenograft models, triptolide and its prodrug derivative minnelide are particularly effective in inhibiting tumor growth. These results demonstrate the key oncogenic role of super-enhancer activity following epigenetic dysfunction in SCCOHT, which can be effectively targeted through inhibition of its functional components, such as TFIIH inhibition with triptolide.

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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

Project description: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. 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 AP-1 activity.

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Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) cell lines treated with triptolide for 6 or 16h - H3K27ac CUT&RUN

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Project description:Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer afflicting young women at a median age of 24 years. SCCOHTs are characterized by loss of protein expression of SWI/SNF chromatin remodeling ATPases SMARCA4 and SMARCA2 through mutation and epigenetic silencing, respectively. This study aims to establish gene expression profiles of this cancer through RNA-Seq of four pathologically confirmed cases of SCCOHT tumors.

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P25_AUAU_Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)

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