The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ

Lei Chang, Luca Azzolin, Daniele Di Biagio, Francesca Zanconato, Giusy Battilana, Romy Lucon Xiccato, Mariaceleste Aragona, Stefano Giulitti, Tito Panciera, Alessandro Gandin, Gianluca Sigismondo, Jeroen Krijgsveld, Matteo Fassan, Giovanna Brusatin, Michelangelo Cordenonsi () and Stefano Piccolo ()
Additional contact information
Lei Chang: University of Padua
Luca Azzolin: University of Padua
Daniele Di Biagio: University of Padua
Francesca Zanconato: University of Padua
Giusy Battilana: University of Padua
Romy Lucon Xiccato: University of Padua
Mariaceleste Aragona: University of Padua
Stefano Giulitti: University of Padua
Tito Panciera: University of Padua
Alessandro Gandin: University of Padua
Gianluca Sigismondo: German Cancer Research Center (DKFZ) and Heidelberg University
Jeroen Krijgsveld: German Cancer Research Center (DKFZ) and Heidelberg University
Matteo Fassan: Surgical Pathology and Cytopathology Unit
Giovanna Brusatin: University of Padua
Michelangelo Cordenonsi: University of Padua
Stefano Piccolo: University of Padua

Nature, 2018, vol. 563, issue 7730, 265-269

Abstract: Abstract 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.

Keywords: High Mechanics; Latrunculin; Smaller Adhesive Areas; MCF10A Cells; Pull-down Experiments (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (7)

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DOI: 10.1038/s41586-018-0658-1

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