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ARID1A loss in neuroblastoma promotes the adrenergic-to-mesenchymal transition by regulating enhancer-mediated gene expression.

ABSTRACT: Mutations in genes encoding SWI/SNF chromatin remodeling complexes are found in approximately 20% of all human cancers, with ARID1A being the most frequently mutated subunit. Here, we show that disruption of ARID1A homologs in a zebrafish model accelerates the onset and increases the penetrance of MYCN-driven neuroblastoma by increasing cell proliferation in the sympathoadrenal lineage. Depletion of ARID1A in human NGP neuroblastoma cells promoted the adrenergic-to-mesenchymal transition with changes in enhancer-mediated gene expression due to alterations in the genomic occupancies of distinct SWI/SNF assemblies, BAF and PBAF. Our findings indicate that ARID1A is a haploinsufficient tumor suppressor in MYCN-driven neuroblastoma, whose depletion enhances tumor development and promotes the emergence of the more drug-resistant mesenchymal cell state.

SUBMITTER: Shi H

PROVIDER: S-EPMC7439613 | biostudies-literature |

REPOSITORIES: biostudies-literature

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ARID1A Loss in Neuroblastoma Promotes the Adrenergic-to-Mesenchymal Transition by Regulating Enhancer-Mediated Gene Expression

Project description:This SuperSeries is composed of the SubSeries listed below.

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ARID1A Loss in Neuroblastoma Promotes the Adrenergic-to-Mesenchymal Transition by Regulating Enhancer-Mediated Gene Expression [RNA-seq]

Project description:Gene mutations in components of SWI/SNF chromatin-remodeling complexes are found in approximately 20% of all human cancers, with ARID1A being the most frequently mutated subunit. In neuroblastoma, sequence alterations of ARID1A were identified in 6% of primary tumors and cell lines, and this gene is hemizygously deleted in at least 87% of cases with chromosome 1p deletion, which almost always accompanies MYCN gene amplification and is the most common deletions in high-risk subtypes of this tumor. However, the role of ARID1A haploinsufficiency in neuroblastoma pathogenesis and the mechanisms involved remain unclear. Here, we show that disruption of ARID1A homologs in a zebrafish model accelerates the onset and increases the penetrance of MYCN-driven neuroblastoma by increasing cell proliferation in the sympathoadrenal lineage. Depletion of ARID1A in human NGP neuroblastoma cells promoted the adrenergic-to-mesenchymal transition with changes in enhancer-mediated gene expression due to alterations in the genomic occupancies of two distinct SWI/SNF assemblies, BAF and PBAF. Our findings indicate that ARID1A is a haploinsufficient tumor suppressor in MYCN-driven neuroblastoma, whose depletion enhances tumor development and promotes the emergence of the more drug resistant mesenchymal cell state.

2020-07-20 | GSE134631 | GEO

ARID1A Loss in Neuroblastoma Promotes the Adrenergic-to-Mesenchymal Transition by Regulating Enhancer-Mediated Gene Expression [ChIP-seq]

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ARID1A Loss in Neuroblastoma Promotes the Adrenergic-to-Mesenchymal Transition by Regulating Enhancer-Mediated Gene Expression

Project description:ARID1A Loss in Neuroblastoma Promotes the Adrenergic-to-Mesenchymal Transition by Regulating Enhancer-Mediated Gene Expression

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ARID1A Loss in Neuroblastoma Promotes the Adrenergic-to-Mesenchymal Transition by Regulating Enhancer-Mediated Gene Expression [ChIP-seq]

Project description:ARID1A Loss in Neuroblastoma Promotes the Adrenergic-to-Mesenchymal Transition by Regulating Enhancer-Mediated Gene Expression [ChIP-seq]

| PRJNA555886 | ENA

ARID1A Loss in Neuroblastoma Promotes the Adrenergic-to-Mesenchymal Transition by Regulating Enhancer-Mediated Gene Expression [RNA-seq]

Project description:ARID1A Loss in Neuroblastoma Promotes the Adrenergic-to-Mesenchymal Transition by Regulating Enhancer-Mediated Gene Expression [RNA-seq]

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Loss of ARID1A Promotes Epithelial-Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress.

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Downregulation of MEG3 promotes neuroblastoma development through FOXO1-mediated autophagy and mTOR-mediated epithelial-mesenchymal transition.

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ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice.

Project description:Genes encoding subunits of SWI/SNF (BAF) chromatin-remodeling complexes are collectively mutated in ∼20% of all human cancers. Although ARID1A is the most frequent target of mutations, the mechanism by which its inactivation promotes tumorigenesis is unclear. Here we demonstrate that Arid1a functions as a tumor suppressor in the mouse colon, but not the small intestine, and that invasive ARID1A-deficient adenocarcinomas resemble human colorectal cancer (CRC). These tumors lack deregulation of APC/β-catenin signaling components, which are crucial gatekeepers in common forms of intestinal cancer. We find that ARID1A normally targets SWI/SNF complexes to enhancers, where they function in coordination with transcription factors to facilitate gene activation. ARID1B preserves SWI/SNF function in ARID1A-deficient cells, but defects in SWI/SNF targeting and control of enhancer activity cause extensive dysregulation of gene expression. These findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as a principal tumor-suppressor function of ARID1A.

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