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SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137404 | GEO | 2020/11/16

REPOSITORIES: GEO

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SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor [ATAC-seq]

Project description:Rhabdoid tumor is a pediatric cancer characterized by the biallelic inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. SMARCB1 inactivation leads to SWI/SNF redistribution to favor a proliferative dedifferentiated cellular state. Although this deletion is the known oncogenic driver, SWI/SNF therapeutic targeting remains a challenge. Here we show mithramycin and a second-generation analogue EC-8042 are effective in this tumor type. Mithramycin evicts SWI/SNF from chromatin triggering a cellular response characterized by chromatin compartment remodeling and promoter reprogramming. These effects lead to differentiation and marked xenograft tumor regressions in vivo. This study provides a therapeutic candidate for rhabdoid tumor and an approach that may be applicable to the more than 20% of cancers characterized by mutated SWI/SNF.

2020-11-16 | GSE137397 | GEO

SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor [RNA-seq]

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SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor [ChIP-seq]

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SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor

Project description:SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor

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SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor [ATAC-seq]

Project description:SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor [ATAC-seq]

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SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor [RNA-seq]

Project description:SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor [RNA-seq]

| PRJNA565377 | ENA

SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor [ChIP-seq]

Project description:SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor [ChIP-seq]

| PRJNA565373 | ENA

Super-Enhancer Dysregulation in Rhabdoid Tumor Cells Is Regulated by the SWI/SNF ATPase BRG1.

Project description:Mutations in the SWI/SNF chromatin remodeling complex occur in ~20% of cancers. In rhabdoid tumors defined by loss of the SWI/SNF subunit SMARCB1, dysregulation of enhancer-mediated gene expression is pivotal in driving oncogenesis. Enhancer dysregulation in this setting is tied to retention of the SWI/SNF ATPase BRG1-which becomes essential in the absence of SMARCB1-but precisely how BRG1 contributes to this process remains unknown. To characterize how BRG1 participates in chromatin remodeling and gene expression in SMARCB1-deficient cells, we performed a genome-wide characterization of the impact of BRG1 depletion in multiple rhabdoid tumor cell lines. We find that although BRG1-regulated open chromatin sites are distinct at the locus level, the biological characteristics of the loci are very similar, converging on a set of thematically related genes and pointing to the involvement of the AP-1 transcription factor. The open chromatin sites regulated by BRG1 colocalize with histone-marked enhancers and intriguingly include almost all super-enhancers, revealing that BRG1 plays a critical role in maintaining super-enhancer function in this setting. These studies can explain the essentiality of BRG1 to rhabdoid tumor cell identity and survival and implicate the involvement of AP-1 as a critical downstream effector of rhabdoid tumor cell transcriptional programs.

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Mammalian SWI/SNF Enzymes and the Epigenetics of Tumor Cell Metabolic Reprogramming.

Project description:Tumor cells reprogram their metabolism to survive and grow in a challenging microenvironment. Some of this reprogramming is performed by epigenetic mechanisms. Epigenetics is in turn affected by metabolism; chromatin modifying enzymes are dependent on substrates that are also key metabolic intermediates. We have shown that the chromatin remodeling enzyme Brahma-related gene 1 (BRG1), an epigenetic regulator, is necessary for rapid breast cancer cell proliferation. The mechanism for this requirement is the BRG1-dependent transcription of key lipogenic enzymes and regulators. Reduction in lipid synthesis lowers proliferation rates, which can be restored by palmitate supplementation. This work has established BRG1 as an attractive target for breast cancer therapy. Unlike genetic alterations, epigenetic mechanisms are reversible, promising gentler therapies without permanent off-target effects at distant sites.

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Tumor suppression via inhibition of SWI/SNF complex-dependent NF-kappaB activation

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

2017-09-22 | GSE93770 | GEO