Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la perte de l'expression des sous-unités ARID1A et ARID1B des complexes BAF favorise le développement rapide d'une tumeur
SWI/SNF chromatin remodelers play critical roles in development and cancer. The causal links between SWI/SNF complex disassembly and carcinogenesis are obscured by redundancy between paralogous components. Canonical BAF (cBAF)-specific paralogs ARID1A and ARID1B are synthetic lethal in some contexts, but simultaneous mutations in both ARID1s are prevalent in cancer. To understand if and how cBAF abrogation causes cancer, we examined the physiological and biochemical consequences of ARID1A/ARID1B loss. In double-knockout liver and skin, aggressive carcinogenesis followed dedifferentiation and hyperproliferation. In double-mutant endometrial cancer, add-back of either induced senescence. Biochemically, residual cBAF subcomplexes resulting from loss of ARID1 scaffolding were unexpectedly found to disrupt a polybromo-containing BAF (pBAF) function. Of 69 mutations in the conserved scaffolding domains of ARID1 proteins observed in human cancer, 37 caused complex disassembly, partially explaining their mutation spectra. ARID1-less, cBAF-less states promote carcinogenesis across tissues, and suggest caution against paralog-directed therapies for ARID1-mutant cancer.
Nature Cancer 2020