Cellular mechanotransduction regulates the interaction between ARID1A in the SWI/SNF complex and YAP/TAZ.
Major finding: Cellular mechanotransduction regulates the interaction between ARID1A in the SWI/SNF complex and YAP/TAZ.
Concept: Under high mechanical stress ARID1A binds to F-actin, reducing its interaction with TAP/TAZ.
Impact: Full activation of YAP/TAZ may require nuclear accumulation of YAP/TAZ and inhibition of ARID1A-SWI/SNF.
ARID1A and other components of the SWI/SNF chromatin remodeling complex are frequently inactivated by genetic alterations in cancer. However, the mechanism by which the SWI/SNF complex suppresses tumorigenesis remains poorly understood. Chang and colleagues found that ARID1A binds to and inhibits the oncogenic transcriptional coactivators YAP and TAZ, resulting in reduced expression YAP/TAZ target genes. Inhibiting YAP/TAZ promoted proliferation and liver tumorigenesis in Arid1a-deficient cells. SWI/SNF has been previously shown to associate with F-actin, and mechanical cell stress increased the association between nuclear F-actin and ARID1A-SWI/SNF, thereby reducing the association between ARID1A and YAP/TAZ. YAP/TAZ binds to the DNA-binding platform TEAD to drive transcription, and ARID1A competed with TEAD for binding to YAP/TAZ. Thus, under high mechanical stress F-actin blocked YAP/TAZ from binding to ARID1A, promoting increased association between YAP/TAZ and TEAD. In contrast, conditions of low mechanical stress favored the interaction between ARID1A and YAP/TAZ. Consistent with these findings, YAP-expressing neurons formed neurospheres more efficiently on stiff extracellular matrix (ECM) than on soft ECM, and depletion of Arid1a rescued the ability to form neurospheres on stiff ECM by enhancing the YAP/TAZ–TEAD interaction independent of mechanostress. Taken together, these findings suggest that full activation of YAP/TAZ requires nuclear accumulation of YAP/TAZ in addition to suppression of ARID1A–SWI/SNF, which can occur via genetic alteration or mechanical stress. Further, these data suggest that the loss of ARID1 in tumor cells may increase the sensitivity to mechanotransduction to promote tumorigenesis.
Chang L, Azzolin L, Di Biagio D, Zanconato F, Battilana G, Xiccato RL, et al. The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ. Nature 2018;563:265–9.
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