Functional annotation of the Hippo pathway somatic mutations in human cancers

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, Zhipeng Meng, Kun-Liang Guan, Ruxi Qi (), Ray Luo () and Wenqi Wang ()
Additional contact information
Han Han: Wuhan University
Zhen Huang: Irvine
Congsheng Xu: Southern University of Science and Technology
Gayoung Seo: Irvine
Jeongmin An: Irvine
Bing Yang: Irvine
Yuhan Liu: Irvine
Tian Lan: Irvine
Jiachen Yan: Irvine
Shanshan Ren: Southern University of Science and Technology
Yue Xu: Wuhan University
Di Xiao: Wuhan University
Jonathan K. Yan: Irvine
Claire Ahn: Irvine
Dmitry A. Fishman: Irvine
Zhipeng Meng: University of Miami Miller School of Medicine
Kun-Liang Guan: Westlake University
Ruxi Qi: Southern University of Science and Technology
Ray Luo: Irvine
Wenqi Wang: Irvine

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract The Hippo pathway is commonly altered in cancer initiation and progression; however, exactly how this pathway becomes dysregulated to promote human cancer development remains unclear. Here we analyze the Hippo somatic mutations in the human cancer genome and functionally annotate their roles in targeting the Hippo pathway. We identify a total of 85 loss-of-function (LOF) missense mutations for Hippo pathway genes and elucidate their underlying mechanisms. Interestingly, we reveal zinc-finger domain as an integral structure for MOB1 function, whose LOF mutations in head and neck cancer promote tumor growth. Moreover, the schwannoma/meningioma-derived NF2 LOF mutations not only inhibit its tumor suppressive function in the Hippo pathway, but also gain an oncogenic role for NF2 by activating the VANGL-JNK pathway. Collectively, our study not only offers a rich somatic mutation resource for investigating the Hippo pathway in human cancers, but also provides a molecular basis for Hippo-based cancer therapy.

Date: 2024
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DOI: 10.1038/s41467-024-54480-y

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