Title | A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Michel BC, D'Avino AR, Cassel SH, Mashtalir N, McKenzie ZM, McBride MJ, Valencia AM, Zhou Q, Bocker M, Soares LMM, Pan J, Remillard DI, Lareau CA, Zullow HJ, Fortoul N, Gray NS, Bradner JE, Chan HMan, Kadoch C |
Journal | Nat Cell Biol |
Volume | 20 |
Issue | 12 |
Pagination | 1410-1420 |
Date Published | 2018 12 |
ISSN | 1476-4679 |
Keywords | Cell Line, Tumor, Cell Proliferation, Chromatin, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, HEK293 Cells, Humans, Mutation, Nuclear Proteins, Promoter Regions, Genetic, Rhabdoid Tumor, RNA Interference, Sarcoma, Synovial, Transcription Factors |
Abstract | Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non-canonical complex (ncBAF). However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma and malignant rhabdoid tumours, which both exhibit cBAF complex (SMARCB1 subunit) perturbation. Chemical and biological depletion of the ncBAF subunit, BRD9, rapidly attenuates synovial sarcoma and malignant rhabdoid tumour cell proliferation. Importantly, in cBAF-perturbed cancers, ncBAF complexes maintain gene expression at retained CTCF-promoter sites and function in a manner distinct from fusion oncoprotein-bound complexes. Together, these findings unmask the unique targeting and functional roles of ncBAF complexes and present new cancer-specific therapeutic targets. |
DOI | 10.1038/s41556-018-0221-1 |
Alternate Journal | Nat. Cell Biol. |
PubMed ID | 30397315 |
PubMed Central ID | PMC6698386 |
Grant List | DP2 CA195762 / CA / NCI NIH HHS / United States R01 CA237241 / CA / NCI NIH HHS / United States T32 GM095450 / GM / NIGMS NIH HHS / United States |
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