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

Author

Listed:
  • 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
    The FIRC Institute for Molecular Oncology)

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.

Suggested Citation

  • Lei Chang & Luca Azzolin & Daniele Di Biagio & Francesca Zanconato & Giusy Battilana & Romy Lucon Xiccato & Mariaceleste Aragona & Stefano Giulitti & Tito Panciera & Alessandro Gandin & Gianluca Sigis, 2018. "The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ," Nature, Nature, vol. 563(7730), pages 265-269, November.
  • Handle: RePEc:nat:nature:v:563:y:2018:i:7730:d:10.1038_s41586-018-0658-1
    DOI: 10.1038/s41586-018-0658-1
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    Citations

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    Cited by:

    1. Sumana Srivatsa & Hesam Montazeri & Gaia Bianco & Mairene Coto-Llerena & Mattia Marinucci & Charlotte K. Y. Ng & Salvatore Piscuoglio & Niko Beerenwinkel, 2022. "Discovery of synthetic lethal interactions from large-scale pan-cancer perturbation screens," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Mintao Ji & Dongsheng Chen & Yinyin Shu & Shuai Dong & Zhisen Zhang & Haimeng Zheng & Xiaoni Jin & Lijun Zheng & Yang Liu & Yifei Zheng & Wensheng Zhang & Shiyou Wang & Guangming Zhou & Bingyan Li & B, 2023. "The role of mechano-regulated YAP/TAZ in erectile dysfunction," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Xinwei Liu & Yingying Ye & Liling Zhu & Xiaoyun Xiao & Boxuan Zhou & Yuanting Gu & Hang Si & Huixin Liang & Mingzhu Liu & Jiaqian Li & Qiongchao Jiang & Jiang Li & Shubin Yu & Ruiying Ma & Shicheng Su, 2023. "Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Hongyu Shen & Xun Huang & Yiheng Zhao & Dongmei Wu & Kaili Xue & Jingfei Yao & Yushuang Wang & Nan Tang & Yifu Qiu, 2022. "The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Kirstin Meyer & Nicholas C. Lammers & Lukasz J. Bugaj & Hernan G. Garcia & Orion D. Weiner, 2023. "Optogenetic control of YAP reveals a dynamic communication code for stem cell fate and proliferation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Cornelis J. Boogerd & Ilaria Perini & Eirini Kyriakopoulou & Su Ji Han & Phit La & Britt Swaan & Jari B. Berkhout & Danielle Versteeg & Jantine Monshouwer-Kloots & Eva Rooij, 2023. "Cardiomyocyte proliferation is suppressed by ARID1A-mediated YAP inhibition during cardiac maturation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Davide Esposito & Ila Pant & Yao Shen & Rui F. Qiao & Xiaobao Yang & Yiyang Bai & Jian Jin & Poulikos I. Poulikakos & Stuart A. Aaronson, 2022. "ROCK1 mechano-signaling dependency of human malignancies driven by TEAD/YAP activation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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