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Characterizing the function of SMARCB1 deficient and proficient SWI/SNF in Epithelioid Sarcoma cell lines by tetON re-expression and small molecule inhibition (BRM014)

ABSTRACT: Characterizing the function of SMARCB1 deficient and proficient SWI/SNF in Epithelioid Sarcoma cell lines by tetON re-expression and small molecule inhibition (BRM014)

PROVIDER: PRJNA1158257 | ENA |

REPOSITORIES: ENA

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Characterizing the function of SMARCB1 deficient and proficient SWI/SNF in Epithelioid Sarcoma cell lines by tetON re-expression and small molecule inhibition (BRM014)

Project description:Several isogenic tetON SMARCB1 re-expressing Epithelioid Sarcoma cell lines alongside bulk empty (MCS) vector transduced controls were submitted to DOX (re-expression) and BRMO014 (inhibition of SWI/SNF)

2024-12-16 | GSE276634 | GEO

Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ChIP-Seq]

Project description:Dysfunction of epigenetic modulators such as the SWI/SNF complex is involved in a wide spectrum of cancer entities, yet their precise role in carcinogenesis is not clear to date Among SWI/SNF-mutant entities, SMARCB1-deficient cancers such as Epithelioid Sarcoma (EpS) are characterized by this genetic event in an otherwise rather silent mutational landscape. However, its oncogenic role remains unclear. Here, we generate a panel of SMARCB1 re-expressing Epithelioid Sarcoma (EpS) cell lines and employ a functional multi-omics approach to characterize and compare the function of the residual SMARCB1-deficient and the physiological SWI/SNF complex in EpS. We show that SWI/SNF holds canonical characteristics of both tumor-suppressors and proto-oncogenes due to its multi-faceted role in the regulation of the epigenome. Our data indicates that the loss of SMARCB1 causes an overall loss of SWI/SNF chromatin affinity at cis-regulatory enhancer elements, inducing a preference for uncontrolled proliferation and cell cycle progression as opposed to development and differentiation. As epigenetic regulation is a dynamic complex, we further demonstrate that EpS cell lines depend on continuous residual SWI/SNF action to maintain clonogenicity and proliferation. Consequently, our models exhibit markedly increased sensitivity to pharmacological inhibition of the residual SWI/SNF when compared with SWI/SNF-proficient cancer entities. Collectively, our results shed new light on the pleiotropic, deregulated pathways upon SWI/SNF dysfunction in EpS and provide inroads for further therapeutic approaches.

2024-11-09 | GSE281436 | GEO

Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ATAC-Seq]

2024-11-09 | GSE281434 | GEO

Transcriptional response to Smarcb1 re-expression in murine derived Smarcb1 deficient p53 null tumors

Project description:SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice. Profiling Smarcb1 dependent gene expression we find genes which are dependent on Smarcb1 expression to be enriched for ECM and cell adhesion functions. We identify Igfbp7, which is related to the insulin-like growth factor binding proteins family, as a downstream target of Smarcb1 transcriptional activity, and show that re-introduction of Igfbp7 alone can hinder tumor development. Two cancer cell lines, 167 and 365, derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice were re-infected with a retro-viral vector for Smarcb1 re-expression or an empty retro-viral vector as control. Total-RNA was collected 3 days post infection so as to enrich for direct targets of Smarcb1 transcriptionaly regulated genes

2013-12-31 | E-GEOD-46017 | biostudies-arrayexpress

Targeting Dependency on a Paralog Pair of CBP/p300 against De-repression of KREMEN2 in SMARCB1-Deficient Cancers

Project description:SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex, is the causative gene of rhabdoid tumors and epithelioid sarcomas. Here, we identify a paralog pair of CBP and p300 as a synthetic lethal target in SMARCB1-deficient cancers by using a dual siRNA screening method based on the “simultaneous inhibition of a paralog pair” concept. Treatment with CBP/p300 dual inhibitors suppresses growth of cell lines and tumor xenografts derived from SMARCB1-deficient cells but not from SMARCB1-proficient cells. SMARCB1-containing SWI/SNF complexes localize with H3K27me3 and its methyltransferase EZH2 at the promotor region of the KREMEN2 locus, resulting in transcriptional downregulation of KREMEN2. By contrast, SMARCB1 deficiency leads to localization of H3K27ac, and recruitment of its acetyltransferases CBP and p300, at the KREMEN2 locus, resulting in transcriptional upregulation of KREMEN2, which cooperates with the SMARCA1 chromatin remodeling complex. Simultaneous inhibition of CBP/p300 leads to transcriptional downregulation of KREMEN2, followed by apoptosis induction via monomerization of KREMEN1 due to a failure to interact with KREMEN2, which suppresses anti-apoptotic signaling pathways. Taken together, our findings indicate that simultaneous inhibitors of CBP/p300 could be promising therapeutic agents for SMARCB1-deficient cancers.

2024-04-29 | GSE237043 | GEO

Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ChIP-Seq]

Project description:Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ChIP-Seq]

| PRJNA1183853 | ENA

Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ATAC-Seq]

Project description:Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ATAC-Seq]

| PRJNA1183856 | ENA

Transcriptional response to Smarcb1 re-expression in murine derived Smarcb1 deficient p53 null tumors

2013-12-31 | GSE46017 | GEO

Global proteomics and SWI/SNF interactomics in Epithelioid Sarcoma (EpS) upon rescue of SMARCB1

Project description:DOX-dependently SMARCB1-re-expressing, stable isogenic EpS cell line models were generated and submitted to global proteomic analysis as well as interactome analysis by co-immunoprecipitation of BRG1, one of the SWI/SNF core ATPases after 96h of DOX treatment.

2024-12-17 | PXD053945 | Pride

Gene expression analysis of human haploid cells (HAP1) depleted of SMARCB1 and SMARCA4

Project description:The aim of this study is to analyze the change in genome wide expression levels in HAP1 cells upon loss of SMARCB1, SMARCA4 or both these genes together. The SMARCB1 and SMARCA4 genes were the hits from a genome wide screen involving genetrap mutagenesis to find new players that are involved in sensitivity to Doxorubicin (Dox). It was found that loss of SMARCB1 and SMARCA4 genes impart resistance in HAP1 cells to Dox. To validate this, the genes were knocked out in HAP1 cells with CRISPR-Cas9 technology. Gene expression levels in SMARCB1 null, SMARCA4 null and SMARCB1-SMARCA4 double null cells were compared to wildtype HAP1 cells using RNAseq. From these experiments it was found that SMARCB1 loss caused several fold increase in ABCB1 gene levels. ABCB1 is an efflux pump in cells responsible for flushing out many small-molecule drugs. Further analysis of this gene confirmed that ABCB1 was the main factor responsible for Dox resistance upon SMARCB1 loss. In total there are four different cell types with two replicates for each cell type. Therefore, 8 samples in total.

2016-08-22 | E-GEOD-75515 | biostudies-arrayexpress

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