A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation.
Nat Cell Biol
; 20(12): 1410-1420, 2018 12.
Article
em En
| MEDLINE
| ID: mdl-30397315
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Cromatina
/
Proteínas Cromossômicas não Histona
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Tumor Rabdoide
/
Sarcoma Sinovial
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Nat Cell Biol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos