A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation

Michel, Brittany C.; D’Avino, Andrew R.; Cassel, Seth H.; Mashtalir, Nazar; McKenzie, Zachary M.; McBride, Matthew J.; Valencia, Alfredo M.; Zhou, Qiang; Bocker, Michael; Soares, Luis M.; Pan, Joshua; Remillard, David; Lareau, Caleb A.; Zullow, Hayley; Fortoul, Nora; Gray, Nathanael S.; Bradner, James E.; Chan, Ho Man; Kadoch, Cigall

doi:10.1038/s41556-018-0221-1

Cited by 317 publications

(391 citation statements)

References 66 publications

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“…The SWI/SNF complex, first characterized in yeast, is best known for its ability to activate gene expression by facilitating formation of nucleosome-depleted regions at gene promoters [3][4][5][6][7] . The mammalian SWI/SNF complex has important roles in development and consists of at least 3 major isoforms: BRG1(SMARCA4)-associated factor (BAF), poly-bromo-BAF (PBAF), and non-canonical BAF (ncBAF), which can either activate or repress gene expression in different contexts [8][9][10][11][12] . These isoforms share a set of core subunits, SMARCC1, SMARCC2, and SMARCD1/2/3.…”

Section: Introductionmentioning

confidence: 99%

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Raupach

Garcia-Mansfield

Sharma

et al. 2019

Preprint

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Chromatin remodeling plays a critical role in tumor suppression as demonstrated by 20% of human cancers bearing inactivating mutations in SWI/SNF chromatin remodeling complex members. Mutations in different SWI/SNF subunits drive a variety of adult and pediatric tumor types, including non-small cell lung cancers, rhabdoid tumors, medulloblastomas, and ovarian cancers. Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is an aggressive subtype of ovarian cancer occurring in young women. Nearly all (>98%) SCCOHTs have inactivating mutations in SMARCA4, which encodes 1 of 2 mutually exclusive catalytic subunits of the SWI/SNF complex. Less than half of SCCOHT patients survive 5 years despite aggressive surgery and multimodal chemotherapy. Empirical support for effective SCCOHT treatments is scarce, in part because of the poor understanding of SCCOHT tumorigenesis. To gain insight into the functional consequences of SWI/SNF subunit loss, we defined SWI/SNF composition and its protein-protein interactions (PPIs) by immunoprecipitation and mass spectrometry (IP-MS) of SWI/SNF subunits in 3 SCCOHT cell lines. Comparing these results to a cell line containing a wild-type SWI/SNF complex, the interaction of most canonical core SWI/SNF subunits was observed in all SCCOHT cell lines at a lower abundance. The SCCOHT SWI/SNF also lacked ATPase module subunits and showed a drastic reduction in PBAF-specific subunit interactions. The wild-type and SCCOHT SWI/SNF subunits immunoprecipitated a shared set of 26 proteins, including core SWI/SNF subunits and RNA processing proteins. We observed 131 proteins exclusively interacting with the wild-type SWI/SNF complex including isoform-specific SWI/SNF subunits, members of the NuRD complex, and members of the MLL3/4 complex. We observed 60 PPIs exclusive to the SCCOHT residual SWI/SNF shared in at least 2 of the 3 SCCOHT cell lines, including many proteins involved in RNA processing. Differential interactions with the residual SWI/SNF complex in SCCOHT may further elucidate altered functional consequences of SMARCA4 mutations in these tumors as well as identify synthetic lethal targets that translate to other SWI/SNF-deficient tumors.Introduction:

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Section: Introductionmentioning

confidence: 99%

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Raupach

Garcia-Mansfield

Sharma

et al. 2019

Preprint

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“…Mutations in SWI/SNF chromatin remodeling genes occur with high frequency in cancer; they are detected in approximately 20% of all cancer patients . The SWI/SNF chromatin remodeling complex is composed of 15 subunits, and it is classified into 3 complexes comprising different subunits (Figure ): the BRG1/BRM‐associated factor (BAF) complex, the polybromo‐associated BAF (PBAF) complex, and the noncanonical BAF (ncBAF) complex . The function of the SWI/SNF chromatin remodeling complex relies on the catalytic activities of the SWI/SNF2‐like ATPase and helicase domains.…”

Section: Genetic Abnormality Of Swi/snf Chromatin Remodeling Genes Inmentioning

confidence: 99%

“…This suggests that the BAF complex containing the SS18‐SSX fusion protein is deficient in SMARCB1 function. SMARCB1‐deficient cancer cells and SS18‐SSX fusion cancer cells are synthetic lethal because of inhibition of a subunit of the ncBAF complex, such as BRD9 . Thus, BAF complex‐deficient cancers, such as SMARCB1‐deficient cancers, depend on the function of the residual ncBAF complex.…”

Section: Synthetic Lethal Targets Based On Targeting the Interaction mentioning

confidence: 99%

“…are synthetic lethal because of inhibition of a subunit of the ncBAF complex, such as BRD9. 18,29,30 Thus, BAF complex-deficient cancers, such as SMARCB1-deficient cancers, depend on the function of the residual ncBAF complex. A BRD9 inhibitor would therefore be a promising strategy for SMARCB1-deficient cancers.…”

Section: Smarcb1-deficient Cancer Cells and Ss18-ssx Fusion Cancer Cellsmentioning

confidence: 99%

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Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex‐deficient cancers

Sasaki

Ogiwara

2020

Cancer Science

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The SWI/SNF chromatin remodeling complex is composed of approximately 15 subunits, and approximately 20% of all cancers carry mutations in the genes encoding these subunits. Most of the genetic alterations in these genes are loss‐of‐function mutations. The identification of vulnerability based on synthetic lethality in cancers with SWI/SNF chromatin remodeling complex deficiency contributes to precision medicine. The SWI/SNF chromatin remodeling complex is involved in transcription, DNA repair, DNA replication, and chromosomal segregation. Cancers with deficiency in the SWI/SNF chromatin remodeling complex show increased vulnerability derived from the loss of these functions. Synthetic lethal targets have been identified based on vulnerabilities in the functions of the SWI/SNF chromatin remodeling complex. In this review article, we propose a precision medicine strategy using chemotherapeutic methods, such as molecular targeted therapy and immunotherapy, based on harnessing synthetic lethality in cancers with deficiency in the SWI/SNF chromatin remodeling complex.

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“…The enzymatic activity of the mSWI/SNF complexes are driven by the ATPase Brahma-related gene 1 (Brg1) or Brahma (Brm) [2,[7][8][9]. There are many associated subunits that combine in an ordered manner [10] to form different subfamilies of complexes that contain both common and unique subunits [10][11][12][13][14]. The great diversity of enzyme complex assemblies is thought to enable cell-and developmental stage-specific functions [14,15].…”

Section: Introductionmentioning

confidence: 99%

CK2-dependent phosphorylation of the Brg1 chromatin remodeling enzyme occurs during mitosis

Padilla‐Benavides

Haokip

Yoon

et al. 2019

Preprint

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Brg1 (Brahma related gene 1) is one of two mutually exclusive ATPases that can act as the catalytic subunit of mammalian SWI/SNF chromatin remodeling enzymes that facilitate utilization of the DNA in eukaryotic cells. Brg1 is a phospho-protein and its activity is regulated by specific kinases and phosphatases. Previously, we showed that Brg1 interacts with and is phosphorylated by casein kinase 2 (CK2) in a manner that regulates myoblast proliferation.Here we demonstrate that the Brg1-CK2 interaction occurred during mitosis in embryonic somites and in primary myoblasts derived from satellite cells isolated from muscle tissue. The interaction of CK2 activity with Brg1 and the incorporation of a number of other subunits into the mSWI/SNF enzyme complex were independent of CK2 enzymatic activity. CK2-mediated hyperphosphorylation of Brg1 was observed in mitotic cells derived from multiple cell types and organisms, suggesting functional conservation across tissues and species. The mitotically hyperphosphorylated form of Brg1 was localized with soluble chromatin, demonstrating that CK2-mediated phosphorylation of Brg1 is associated with specific partitioning of Brg1 within sub-cellular compartments. Thus CK2 acts a mitotic kinase that regulates Brg1 phosphorylation and sub-cellular localization.function of Brg1 and leads to a block of myogenic differentiation [16]. However, dephosphorylation of Brg1 by the phosphatase, calcineurin, opposes the activity of PKCβ1, allowing chromatin remodeling by Brg1 and initiation of myogenesis [16]. Mutagenesis and unbiased mass spectrometry analyses of Brg1 phosphopeptides in the presence and absence of a calcineurin inhibitor identified calcineurin target sequences, but the mass spectrometry data identified additional Brg1 phosphopeptides that were not responsive to calcineurin inhibition [16]. This suggested that Brg1 is a target of additional signal transduction pathways. Our subsequent studies showed that Brg1 was phosphorylated by casein kinase 2 (CK2), a Serine/Threonine kinase, which promoted myoblast proliferation and survival by regulating subnuclear localization and incorporation of one of two related subunits, BAF155/BAF170, into the enzyme complex [17].CK2 is ubiquitously expressed and functions as a tetramer of two catalytic subunits, CK2α or CK2α', and two CK2β regulatory subunits, and it has more than 300 known substrates [29][30][31].CK2 is required for cell cycle progression, survival, apoptosis, and transcriptional regulation.Knockout mice lacking the CK2α subunit show cardiac and neural tube defects and die during embryogenesis, whereas mice lacking the α' subunit have impaired spermatogenesis [32][33][34].Knockout of the CK2β subunit in mice leads to reduced proliferation during embryogenesis, which is reflected in the small size of the animals at embryonic day 6.5 (E6.5) and resorption at E7.5 [35]. Analyses of a murine conditional knockout model showed that CK2β is essential for viability of embryonic stem cells and primary embryonic fibroblasts [35]. In vitro ...

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A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation

Cited by 317 publications

References 66 publications

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex‐deficient cancers

CK2-dependent phosphorylation of the Brg1 chromatin remodeling enzyme occurs during mitosis

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