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SWI/SNF complex mutations promote thyroid tumor progression and resistance to redifferentiation therapy (RNA-seq, Fig3)

ABSTRACT: Recurrent mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex occur commonly in human cancers of different lineages, including advanced thyroid cancers. Thyroid-specific loss of Arid1a, Arid2 or Smarcb1 in mouse BrafV600E-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. Swi/Snf loss leads to a repressive chromatin state at thyroid lineage transcription factors and their target binding sites, resulting in impaired expression of genes required for thyroid hormone biosynthesis. Thyroid differentiation and response to radioiodine therapy is restored by MAPK inhibitors in mouse BrafV600E-mutant thyroid cancers, which is abrogated in the context of Swi/Snf loss. MAPK inhibitors also failed to restore thyroid differentiation and radioiodide incorporation in patients with BRAFV600E or RAS-mutant tumors with SWI/SNF mutations. SWI/SNF complexes are central to the maintenance of differentiated thyroid function, and their loss confers RAI refractoriness and resistance to MAPK inhibitor-based redifferentiation therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE147478 | GEO | 2020/12/02

REPOSITORIES: GEO

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SWI/SNF complex mutations promote thyroid tumor progression and resistance to redifferentiation therapy [RNA-seq]

Project description:Recurrent mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex occur commonly in human cancers of different lineages, including advanced thyroid cancers. Thyroid-specific loss of Arid1a, Arid2 or Smarcb1 in mouse BrafV600E-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. Swi/Snf loss leads to a repressive chromatin state at thyroid lineage transcription factors and their target binding sites, resulting in impaired expression of genes required for thyroid hormone biosynthesis. Thyroid differentiation and response to radioiodine therapy is restored by MAPK inhibitors in mouse BrafV600E-mutant thyroid cancers, which is abrogated in the context of Swi/Snf loss. MAPK inhibitors also failed to restore thyroid differentiation and radioiodide incorporation in patients with BRAFV600E or RAS-mutant tumors with SWI/SNF mutations. SWI/SNF complexes are central to the maintenance of differentiated thyroid function, and their loss confers RAI refractoriness and resistance to MAPK inhibitor-based redifferentiation therapies.

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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.

2024-01-21 | PXD046276 | Pride

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

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

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Targeting DCAF5 suppresses SMARCB1-mutant cancer via stabilizing SWI/SNF

Project description:While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and presents a conundrum for precision therapy because the proteins are no longer present. SMARCB1-mutant cancers epitomize this challenge because these highly lethal cancers are driven by inactivation of a single gene, a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to seek vulnerabilities, we contributed 16 SMARCB1-mutant cell lines to a near-genomewide CRISPR screen as part of the Cancer Dependency Map1-3. Here we report that the little-studied gene DCAF5 (DDB1-CUL4 Associated Factor 5) is a specific dependency in SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and in the absence of SMARCB1 DCAF5 causes degradation of incompletely assembled SWI/SNF complexes. Upon inhibition of DCAF5 SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore gene expression to levels sufficient to fully reverse the cancer state, including in a xenograft mouse model. 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 DCAF5 may be sufficient to restore substantial SWI/SNF function and reverse cancer phenotypes caused by SMARCB1 loss.

2024-03-22 | GSE215024 | GEO

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