ATAC-seq in ARID1A WT or KO OVCA429 Cells after interferron treatment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE131915 | GEO | 2020/05/06
REPOSITORIES: GEO
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Project description:Whether cancer driver mutation(s) directly drives cancer immune phenotype and immune tolerance remains a standing question. ARID1A is a core member of the polymorphic BAF chromatin remodeling complex. ARID1A mutations frequently occur in human cancers and drive cancer development. Here, we studied the molecular, cellular, and clinical impact of ARID1A gene status on cancer immunity. We demonstrate that ARID1A mutations, limited expression, and deficiency impair interferon(IFN)-responsive gene chromatin accessibility and expression, resulting in anemic T cell tumor infiltration, weakened tumor immunity, and shortened host survival in many human cancer histologies as well as in murine cancer models, and are negatively associated with immunotherapy response. Mechanistically, ARID1A interacts with EZH2 via its carboxyl terminal and antagonizes EZH2-mediated IFN responsiveness. Thus, the interaction between ARID1A and EZH2 defines cancer IFN-responsiveness and immune evasion. Our work indicates that cancer epigenetic driver mutations can shape cancer immune phenotype and immunotherapy.
2020-05-06 | GSE131917 | GEO
Project description:Whether cancer driver mutation(s) directly drives cancer immune phenotype and immune tolerance remains a standing question. ARID1A is a core member of the polymorphic BAF chromatin remodeling complex. ARID1A mutations frequently occur in human cancers and drive cancer development. Here, we studied the molecular, cellular, and clinical impact of ARID1A gene status on cancer immunity. We demonstrate that ARID1A mutations, limited expression, and deficiency impair interferon(IFN)-responsive gene chromatin accessibility and expression, resulting in anemic T cell tumor infiltration, weakened tumor immunity, and shortened host survival in many human cancer histologies as well as in murine cancer models, and are negatively associated with immunotherapy response. Mechanistically, ARID1A interacts with EZH2 via its carboxyl terminal and antagonizes EZH2-mediated IFN responsiveness. Thus, the interaction between ARID1A and EZH2 defines cancer IFN-responsiveness and immune evasion. Our work indicates that cancer epigenetic driver mutations can shape cancer immune phenotype and immunotherapy.
2020-05-06 | GSE131916 | GEO
Project description:ARID1A is a core protein subunit of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex and among the most frequently mutated tumor suppressors in human cancers. Immune checkpoint blockade (ICB) clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to ICB in a number of solid tumor types in a manner that is independent of microsatellite instability. However, the molecular mechanisms that promote improved ICB response in ARID1A mutant tumors remain incompletely understood. We developed ARID1A deficient murine tumor models that exhibit anti-tumor immune phenotypes such as increased CD8+ T cell infiltration and activation observed in ARID1A mutant human cancers. Leveraging these tumor models and public transcriptomic datasets, we discovered that ARID1A deficient cancers display upregulation of an immunogenic interferon (IFN) gene expression signature, including genes known to mediate T/NK cell recruitment and activation. ARID1A loss increased cytosolic single stranded DNA (ssDNA) and cytosolic RNA:DNA hybrids which are known to induce IFN via viral mimicry and were associated with increased presence of R-Loops as a result of transcription-replication conflicts during DNA replication. Accordingly, overexpression of the R-Loop resolving enzyme, RNaseH2B, or the cytosolic DNase, TREX1, restores ARID1A loss induced interferon stimulated gene (ISG) upregulation to control levels. Furthermore, we demonstrate that the ARID1A-IFN gene expression signature and anti-tumor immunity is driven by STING dependent cytosolic DNA sensing and Type I IFN, which is requirement for the improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings represent a novel molecular mechanism underlying anti-tumor immunity in ARID1A-mutant cancers and may have translational utility in improving patient selection for ICB.
2024-04-06 | GSE217804 | GEO
Project description:ARID1A is a core protein subunit of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex and among the most frequently mutated tumor suppressors in human cancers. Immune checkpoint blockade (ICB) clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to ICB in a number of solid tumor types in a manner that is independent of microsatellite instability. However, the molecular mechanisms that promote improved ICB response in ARID1A mutant tumors remain incompletely understood. We developed ARID1A deficient murine tumor models that exhibit anti-tumor immune phenotypes such as increased CD8+ T cell infiltration and activation observed in ARID1A mutant human cancers. Leveraging these tumor models and public transcriptomic datasets, we discovered that ARID1A deficient cancers display upregulation of an immunogenic interferon (IFN) gene expression signature, including genes known to mediate T/NK cell recruitment and activation. ARID1A loss increased cytosolic single stranded DNA (ssDNA) and cytosolic RNA:DNA hybrids which are known to induce IFN via viral mimicry and were associated with increased presence of R-Loops as a result of transcription-replication conflicts during DNA replication. Accordingly, overexpression of the R-Loop resolving enzyme, RNaseH2B, or the cytosolic DNase, TREX1, restores ARID1A loss induced interferon stimulated gene (ISG) upregulation to control levels. Furthermore, we demonstrate that the ARID1A-IFN gene expression signature and anti-tumor immunity is driven by STING dependent cytosolic DNA sensing and Type I IFN, which is requirement for the improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings represent a novel molecular mechanism underlying anti-tumor immunity in ARID1A-mutant cancers and may have translational utility in improving patient selection for ICB.
2024-04-06 | GSE217803 | GEO
Project description:ARID1A is a core protein subunit of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex and among the most frequently mutated tumor suppressors in human cancers. Immune checkpoint blockade (ICB) clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to ICB in a number of solid tumor types in a manner that is independent of microsatellite instability. However, the molecular mechanisms that promote improved ICB response in ARID1A mutant tumors remain incompletely understood. We developed ARID1A deficient murine tumor models that exhibit anti-tumor immune phenotypes such as increased CD8+ T cell infiltration and activation observed in ARID1A mutant human cancers. Leveraging these tumor models and public transcriptomic datasets, we discovered that ARID1A deficient cancers display upregulation of an immunogenic interferon (IFN) gene expression signature, including genes known to mediate T/NK cell recruitment and activation. ARID1A loss increased cytosolic single stranded DNA (ssDNA) and cytosolic RNA:DNA hybrids which are known to induce IFN via viral mimicry and were associated with increased presence of R-Loops as a result of transcription-replication conflicts during DNA replication. Accordingly, overexpression of the R-Loop resolving enzyme, RNaseH2B, or the cytosolic DNase, TREX1, restores ARID1A loss induced interferon stimulated gene (ISG) upregulation to control levels. Furthermore, we demonstrate that the ARID1A-IFN gene expression signature and anti-tumor immunity is driven by STING dependent cytosolic DNA sensing and Type I IFN, which is requirement for the improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings represent a novel molecular mechanism underlying anti-tumor immunity in ARID1A-mutant cancers and may have translational utility in improving patient selection for ICB.
2024-04-06 | GSE217805 | GEO
Project description:ARID1A is a core protein subunit of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex and among the most frequently mutated tumor suppressors in human cancers. Immune checkpoint blockade (ICB) clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to ICB in a number of solid tumor types in a manner that is independent of microsatellite instability. However, the molecular mechanisms that promote improved ICB response in ARID1A mutant tumors remain incompletely understood. We developed ARID1A deficient murine tumor models that exhibit anti-tumor immune phenotypes such as increased CD8+ T cell infiltration and activation observed in ARID1A mutant human cancers. Leveraging these tumor models and public transcriptomic datasets, we discovered that ARID1A deficient cancers display upregulation of an immunogenic interferon (IFN) gene expression signature, including genes known to mediate T/NK cell recruitment and activation. ARID1A loss increased cytosolic single stranded DNA (ssDNA) and cytosolic RNA:DNA hybrids which are known to induce IFN via viral mimicry and were associated with increased presence of R-Loops as a result of transcription-replication conflicts during DNA replication. Accordingly, overexpression of the R-Loop resolving enzyme, RNaseH2B, or the cytosolic DNase, TREX1, restores ARID1A loss induced interferon stimulated gene (ISG) upregulation to control levels. Furthermore, we demonstrate that the ARID1A-IFN gene expression signature and anti-tumor immunity is driven by STING dependent cytosolic DNA sensing and Type I IFN, which is requirement for the improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings represent a novel molecular mechanism underlying anti-tumor immunity in ARID1A-mutant cancers and may have translational utility in improving patient selection for ICB.
2024-04-06 | GSE217806 | GEO
Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.
2015-01-20 | E-GEOD-54979 | biostudies-arrayexpress
Project description:Metastatic urothelial carcinoma of the bladder is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A inactivating mutations present in 20% of tumors. EZH2 is a histone methyltransferase that acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in over 20% of bladder cancers. Here we show that ARID1A-mutant tumors are more sensitive to EZH2 inhibition than ARID1A-wild-type tumors. Mechanistic studies reveal that: 1) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via upregulation of a non-canonical PI3K regulatory subunit PIK3R3, and: 2) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, an inhibitor protein of PI3K signaling. Thus, our studies suggest that a subset of bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K, and reveal novel mechanistic insights into the role of non-canonical PI3K constituents in bladder cancer biology.
2022-08-22 | GSE183777 | GEO
Project description:The SWI/SNF chromatin remodeling complex is altered in ~20% of human cancers. ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator in human cancers. Inactivation of the SWI/SNF complex is synthetically lethal with inhibition of EZH2 activity. EZH2 inhibitors are entering clinical trials for specific tumor types with SWI/SNF mutations. However, mechanisms of de novo or acquired resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations are unknown. Here we show that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells.
2019-02-10 | GSE110448 | GEO
Project description:The SWI/SNF chromatin remodeling complex is altered in ~20% of human cancers. ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator in human cancers. Inactivation of the SWI/SNF complex is synthetically lethal with inhibition of EZH2 activity. EZH2 inhibitors are entering clinical trials for specific tumor types with SWI/SNF mutations. However, mechanisms of de novo or acquired resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations are unknown. Here we show that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells.
2019-02-10 | GSE110449 | GEO