Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nat Cancer. 2020 Sep;1(9):909-922. doi: 10.1038/s43018-020-00109-0. Epub 2020 Sep 7.
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.
SWI/SNF 染色质重塑因子在发育和癌症中发挥着关键作用。由于同源成分之间的冗余，SWI/SNF 复合物的解体与致癌之间的因果关系变得模糊不清。在某些情况下，经典的 cBAF 特异性同源物 ARID1A 和 ARID1B 是合成致死的，但在癌症中同时存在两个 ARID1 的突变很常见。为了了解 cBAF 缺失是否以及如何导致癌症，我们研究了 ARID1A/ARID1B 缺失的生理和生化后果。在双敲除的肝脏和皮肤中，去分化和过度增殖后出现侵袭性致癌作用。在双突变的子宫内膜癌中，添加任何一种都会诱导衰老。从生化角度来看，由于 ARID1 支架缺失导致的剩余 cBAF 亚复合物出乎意料地发现会破坏多溴素包含的 pBAF 功能。在人类癌症中观察到的 ARID1 蛋白保守支架结构域中的 69 个突变中的 37 个导致复合物解体，部分解释了它们的突变谱。缺乏 ARID1 和 cBAF 的状态促进了跨组织的癌变，并表明在针对 ARID1 突变癌症的治疗中应谨慎使用同源物导向疗法。
