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YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis

Author

Listed:
  • Zhengming Wu

    (University of California)

  • Junhui Su

    (Fudan University)

  • Fu-long Li

    (Zhejiang University)

  • Tao Chen

    (Tongji University)

  • Jaimie Mayner

    (University of California)

  • Adam Engler

    (University of California)

  • Shenghong Ma

    (Wellcome Sanger Institute)

  • Qingquan Li

    (Fudan University)

  • Kun-Liang Guan

    (University of California
    Westlake University)

Abstract

Small cell lung cancer (SCLC) is highly lethal due to its prevalent metastasis. Most SCLCs have inactivating mutations in TP53 and RB1. We find that loss of YAP expression is key for SCLC cells to acquire rapid ameboid migration and high metastatic potential. YAP functions through its target genes CCN1/CCN2 to inhibit SCLC ameboid migration. RB1 mutation contributes to YAP transcriptional silencing via E2F7, which recruits the RCOR co-repressor complex to YAP promoter. We discover that benzamide family HDAC inhibitors stimulate YAP expression by inhibiting the RCOR-HDAC complex, thereby suppressing SCLC metastasis and improving survival in a mouse model. Our study unveils the molecular and cellular basis underlying SCLC’s high metastatic potential, the previously unrecognized role of YAP in suppressing ameboid migration and tumor metastasis, and the mechanism of YAP transcription regulation involving E2F7, RCOR, and Sin3 HDAC. This study reveals a therapeutic potential of benzamides for SCLC treatment.

Suggested Citation

  • Zhengming Wu & Junhui Su & Fu-long Li & Tao Chen & Jaimie Mayner & Adam Engler & Shenghong Ma & Qingquan Li & Kun-Liang Guan, 2023. "YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41585-z
    DOI: 10.1038/s41467-023-41585-z
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    References listed on IDEAS

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    1. Minzhe Guo & Michael P. Morley & Cheng Jiang & Yixin Wu & Guangyuan Li & Yina Du & Shuyang Zhao & Andrew Wagner & Adnan Cihan Cakar & Michal Kouril & Kang Jin & Nathan Gaddis & Joseph A. Kitzmiller & , 2023. "Guided construction of single cell reference for human and mouse lung," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Yan Ting Shue & Alexandros P. Drainas & Nancy Yanzhe Li & Sarah M. Pearsall & Derrick Morgan & Nasa Sinnott-Armstrong & Susan Q. Hipkins & Garry L. Coles & Jing Shan Lim & Anthony E. Oro & Kathryn L. , 2022. "A conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
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    Cited by:

    1. Han Han & Zhen Huang & Congsheng Xu & Gayoung Seo & Jeongmin An & Bing Yang & Yuhan Liu & Tian Lan & Jiachen Yan & Shanshan Ren & Yue Xu & Di Xiao & Jonathan K. Yan & Claire Ahn & Dmitry A. Fishman & , 2024. "Functional annotation of the Hippo pathway somatic mutations in human cancers," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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