Inactivation of ARID1A and other components of the nuclear SWI/SNF protein complex occurs at very high frequencies in a variety of human malignancies, suggesting a widespread role for the SWI/SNF complex in tumour suppression1. However, the underlying mechanisms remain poorly understood. Here we show that ARID1A-containing SWI/SNF complex (ARID1A–SWI/SNF) operates as an inhibitor of the pro-oncogenic transcriptional coactivators YAP and TAZ2. Using a combination of gain- and loss-of-function approaches in several cellular contexts, we show that YAP/TAZ are necessary to induce the effects of the inactivation of the SWI/SNF complex, such as cell proliferation, acquisition of stem cell-like traits and liver tumorigenesis. We found that YAP/TAZ form a complex with SWI/SNF; this interaction is mediated by ARID1A and is alternative to the association of YAP/TAZ with the DNA-binding platform TEAD. Cellular mechanotransduction regulates the association between ARID1A–SWI/SNF and YAP/TAZ. The inhibitory interaction of ARID1A–SWI/SNF and YAP/TAZ is predominant in cells that experience low mechanical signalling, in which loss of ARID1A rescues the association between YAP/TAZ and TEAD. At high mechanical stress, nuclear F-actin binds to ARID1A–SWI/SNF, thereby preventing the formation of the ARID1A–SWI/SNF–YAP/TAZ complex, in favour of an association between TEAD and YAP/TAZ. We propose that a dual requirement must be met to fully enable the YAP/TAZ responses: promotion of nuclear accumulation of YAP/TAZ, for example, by loss of Hippo signalling, and inhibition of ARID1A–SWI/SNF, which can occur either through genetic inactivation or because of increased cell mechanics. This study offers a molecular framework in which mechanical signals that emerge at the tissue level together with genetic lesions activate YAP/TAZ to induce cell plasticity and tumorigenesis.
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Mass spectrometry data can be found in Supplementary Table 1. Source Data for Figs. 1, 2, 4 and Extended Data Figs. 2–5, 7, 8 can be found in the online version of the paper. Uncropped images of immunoblots can be found in Supplementary Fig. 1. All relevant data are included in the manuscript as Source Data or Supplementary Information; all other data are available from the corresponding authors upon reasonable request.
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We thank A. Fujimura for help with neuron preparation; G. Della Giustina for micropattern fabrication; V. Guzzardo for histology; C. Frasson and G. Basso for FACS; D. M. Livingston for HMECs and plasmids; D. J. Pan, M. Giovannini, Z. Wang, P. Chambon, and I. De Curtis and R. Brambilla for gifts of mice; R. Treisman for ACTB (encoding β-actin) cDNAs; L. Naldini for plasmids; S. Dupont for performing the initial experiments leading to biochemical identification of SWI/SNF and for the protocol to perform F-actin pull-down; Gianluca Grenci and Mona Suryana (MBI-Singapore) and the MBI microfabrication facility team for the supply of quartz masks. This work is supported by AIRC Special Program Molecular Clinical Oncology ‘5 per mille’, by an AIRC PI-Grant, by a MIUR-FARE grant, and by Epigenetics Flagship project CNR-MIUR grants to S.P. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (DENOVOSTEM grant agreement No 670126 to S.P.).
Nature thanks M. Sudol, P. Wade and the other anonymous reviewer(s) for their contribution to the peer review of this work.