Open AccessThe SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ
Author(s) -
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 Cordesi,
Stefano Piccolo
Publication year - 2018
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-018-0658-1
Subject(s) - swi/snf , arid1a , transcription factor , microbiology and biotechnology , biology , smarcb1 , carcinogenesis , chromatin structure remodeling (rsc) complex , hippo signaling pathway , suppressor , genetics , effector , chromatin remodeling , gene , mutation
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 suppression 1 . 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 TAZ 2 . 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.