Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes

Zixi Wang, Kenian Chen, Yuemeng Jia, Jen Chieh Chuang, Xuxu Sun, Yu Hsuan Lin, Cemre Celen, Lin Li, Fang Huang, Xin Liu, Diego H. Castrillon, Tao Wang, Hao Zhu

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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 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 physiologic and biochemical consequences of ARID1A/ARID1B loss. In double knockout liver and skin, aggressive carcinogenesis followed de-differentiation 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 polybromo containing pBAF function. 37 of 69 mutations in the conserved scaffolding domains of ARID1 proteins observed in human cancer 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.

Original languageEnglish (US)
Pages (from-to)909-922
Number of pages14
JournalNature Cancer
Issue number9
StatePublished - Sep 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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