The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ.
The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ.
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DOI：
10.1038/s41586-018-0658-1
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发表时间：
2018-11
期刊：
影响因子：
64.8
通讯作者：
Piccolo S
中科院分区：
文献类型：
--
作者：
Chang L;Azzolin L;Di Biagio D;Zanconato F;Battilana G;Lucon Xiccato R;Aragona M;Giulitti S;Panciera T;Gandin A;Sigismondo G;Krijgsveld J;Fassan M;Brusatin G;Cordenonsi M;Piccolo S
ARID 1A和核SWI/SNF蛋白复合物的其他组分的失活在多种人类恶性肿瘤中以极高的频率发生，表明SWI/SNF在肿瘤抑制中的广泛作用。然而，对潜在的机制仍然知之甚少。在这里，我们表明，ARID 1A含有SWI/SNF复合物（ARID 1A/SWI/SNF）作为抑制剂的原癌转录辅激活因子雅普和TAZ。通过在几种细胞环境中功能获得和丧失方法的组合，我们发现雅普/TAZ有助于展开SWI/SNF失活的作用，如细胞增殖、获得干细胞样性状和肝肿瘤发生。我们发现雅普/TAZ与SWI/SNF复合;这种相互作用是由ARID 1A介导的，并替代雅普/TAZ与其DNA结合平台TEAD的结合。细胞机械转导调节ARID 1A/SWI/SNF和雅普/TAZ之间的关联。ARID 1A/SWI/SNF-雅普/TAZ抑制性相互作用在经历低机械信号传导的细胞中占主导地位，其中ARID 1A的缺失挽救了雅普/TAZ与TEAD的缔合。在高机械应力下，核F-肌动蛋白结合ARID 1A/SWI/SNF，阻止ARID 1A/SWI/SNF-雅普/TAZ复合物的形成，有利于TEAD/雅普/TAZ缔合。我们建议，必须满足双重要求，以充分授权雅普/TAZ反应：促进雅普/TAZ核积累，例如，通过Hippo信号传导的丧失和ARID 1A/SWI/SNF的抑制，如通过基因失活或升高的细胞机制获得的。这项工作提供了一个分子框架，其中机械信号出现在组织水平和遗传病变合谋激活雅普/TAZ诱导细胞可塑性和肿瘤发生。
Inactivation of ARID1A and other components of the nuclear SWI/SNF protein complex occurs at exceedingly high frequency in a variety of human malignancies, suggesting a widespread role for SWI/SNF in tumor suppression. However, the underlying mechanisms remain poorly understood. Here we show that ARID1A-containing SWI/SNF complex (ARID1A/SWI/SNF) operates as inhibitor of the pro-oncogenic transcriptional coactivators YAP and TAZ. By a combination of gain and loss of function approaches in several cellular contexts, we uncovered that YAP/TAZ are instrumental for unfolding the effects of SWI/SNF inactivation, such as cell proliferation, acquisition of stem cell-like traits, and liver tumorigenesis. We found YAP/TAZ in complex with SWI/SNF; this interaction is mediated by ARID1A and alternative to YAP/TAZ association to their DNA-binding platform TEAD. Cellular mechanotransduction regulates the association between ARID1A/SWI/SNF and YAP/TAZ. The ARID1A/SWI/SNF-YAP/TAZ inhibitory interaction is predominant in cells experiencing low mechanical signaling, where loss-of-ARID1A rescues YAP/TAZ association to TEAD. At high mechanical stress, nuclear F-actin binds to ARID1A/SWI/SNF preventing the formation of the ARID1A/SWI/SNF-YAP/TAZ complex, in favor of TEAD/YAP/TAZ association. We propose that a dual requirement must be met to fully empower YAP/TAZ responses: promotion of YAP/TAZ nuclear accumulation, e.g., by loss of Hippo signaling, and inhibition of ARID1A/SWI/SNF, as obtained by either genetic inactivation or raised cell mechanics. This work offers a molecular framework whereby mechanical signals emerging at the tissue level and genetic lesions conspire to activate YAP/TAZ to induce cell plasticity and tumorigenesis.
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DOI：
10.1073/pnas.032662899
发表时间：
2002-03-05
影响因子：
11.1
作者：
Rando, OJ;Zhao, KJ;Crabtree, GR
通讯作者：
Crabtree, GR
影响因子：
56.9
作者：
Baarlink, Christian;Wang, Haicui;Grosse, Robert
通讯作者：
Grosse, Robert
影响因子：
64.5
作者：
Eroglu, Elif;Burkard, Thomas R.;Knoblich, Juergen A.
通讯作者：
Knoblich, Juergen A.
影响因子：
8.8
作者：
Skibinski A;Breindel JL;Prat A;Galván P;Smith E;Rolfs A;Gupta PB;LaBaer J;Kuperwasser C
通讯作者：
Kuperwasser C
影响因子：
64.5
作者：
Azzolin, Luca;Panciera, Tito;Piccolo, Stefano
通讯作者：
Piccolo, Stefano