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Gene expression in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) cell line COV434

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 SMARCA4 loss plays in SCCOHT tumorigenesis, we performed RNA-seq in a SCCOHT cell line +/- SMARCA4 re-expression. SMARCA4 re-expression was acheived by integration of pIND20-BRG1 and inducing with doxycycline. The goal of this study was to generate a high sequencing depth RNA-seq dataset to determine how restoration of SMARCA4 results in changes in gene expression and RNA splicing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217699 | GEO | 2025/04/02

REPOSITORIES: GEO

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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

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CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary (II)

Project description:Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16INK4a-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically.

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

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