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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281436 | GEO | 2024/11/09

REPOSITORIES: GEO

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

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Project description:Here we performed transcriptional profiling of the prostate cancer cell lines LNCaP and 22Rv1 comparing non-targeting siRNA treatment versus siRNAs targeting SWI/SNF complex proteins (SMARCA2, SMARCA4, and SMARCB1). Goal was to determine the effect of SWI/SNF knockdown on gene expression in prostate cancer. Two-condition experiment: non-targeting siRNA versus SWI/SNF-siRNA treated cells. Three SWI/SNF proteins were targeted: SMARCA2, SMARCA4, and SMARB1. Biological replicates: 1 control replicate, 2 treatment replicates per SWI/SNF protein. Technical replicates: 1 replicate per SWI/SNF protein. Cell lines: 22Rv1 and LNCaP.

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BRD9 defines a novel SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors [RNA-seq 2]

Project description:Bromodomain-containing protein 9 (BRD9) was recently identified to be associated with the chromatin remodeling SWI/SNF(BAF) complex, yet its function within the complex has remained unclear. Here, using genome-scale CRISPR-Cas9 screens, we found that BRD9 constitutes a specific vulnerability in highly malignant pediatric rhabdoid tumors, which are driven by inactivating mutations of SMARCB1 subunit of SWI/SNF complexes. Surprisingly, we found that BRD9 does not belong to the previously identified BAF or PBAF complexes, but instead is found exclusively in a novel of SWI/SNF sub-complex. We show that BRD9-containing complexes lack SMARCB1, which had previously been considered a core subunit present in all SWI/SNF variants. We recently demonstrated that both SMARCB1-containing and ARID1A-containing SWI/SNF complexes preferentially function at enhancers, but here we show that BRD9-containing complexes are located at active promoters as well as enhancers. We show that loss of SMARCB1, as observed in rhabdoid tumors, results in increased BRD9 interaction with SWI/SNF core subunit SMARCC1, consistent with competition between SMARCB1 and BRD9 in the formation of SWI/SNF complexes. Underlying the dependency, we demonstrate that BRD9, via its DUF3512 domain, is essential for maintaining the integrity of its sub-complex, which predominates in the absence of SMARCB1. Taken together, our results reveal a BRD9-containing SWI/SNF subcomplex which is required for the survival of SMARCB1-mutant rhabdoid tumors.

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BRD9 defines a novel SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors [ChIP-seq]

2019-03-14 | GSE120234 | GEO

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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

A quality control factor for chromatin complexes is synthetic lethal in SMARCB1-mutant cancers

Project description:While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and is problematic because the tumor suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. Here, we report that the little-studied gene DDB1-CUL4 Associated Factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and promotes degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. Upon depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore SWI/SNF-mediated gene expression to levels sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality control factors may effectively reverse the malignant state of some cancers driven by disruption of tumor suppressor complexes.

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2024-01-21 | PXD046275 | Pride

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Functional interplay between SWI/SNF complexes underlies BRD9 dependency in SMARCB1-mutant cancers [RNA-seq]

Project description:Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in >20% of cancers. SWI/SNF complexes exist in three distinct families that each contribute to regulation of transcription, although the functional interactions between the families are not well understood. Rhabdoid tumors constitute an informative model system as these highly aggressive cancers are driven by inactivation of a single SWI/SNF subunit, SMARCB1, which is present in two SWI/SNF families (cBAF and PBAF) but not in the third (GBAF/ncBAF). We and others have shown that BRD9, a therapeutically targetable member of ncBAF, is essential specifically in SMARCB1-deficient cancers, suggesting key functional relationships between SMARCB1-containing complexes and BRD9/ncBAF. However, the mechanistic underpinnings of these relationships are poorly understood. Here, we demonstrate that genomic binding of BRD9 is largely dependent upon SMARCB1 such that the absence of SMARCB1 results in significantly reduced BRD9 binding. At select sites, however, we show that SMARCB1-loss results in gain of BRD9 binding and BRD9-dependent accessibility. We find that this gain is associated with expression of genes promoting cell migration. Our results define relationships between SWI/SNF complex families, elucidate mechanisms by which SMARCB1 loss drives oncogenesis, and provide mechanistic insight into the synthetic-lethal relationship between SMARCB1 and BRD9.

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