Functional annotation of the Hippo pathway somatic mutations in human cancers
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.
Authors
- Bing Yang (ORCID: https://orcid.org/0000-0002-9355-2538)
- Dmitry A. Fishman (ORCID: https://orcid.org/0000-0001-6287-2128)
- Jiong Yan (ORCID: https://orcid.org/0000-0003-0536-8130)
- Ruxi Qi (ORCID: https://orcid.org/0000-0002-9243-1259)
- Kun‐Liang Guan (ORCID: https://orcid.org/0000-0003-1892-0174)
- Zhen Huang (ORCID: https://orcid.org/0000-0002-8908-0355)
- Congsheng Xu
- Ray Luo (ORCID: https://orcid.org/0000-0002-6346-8271)
- Di Xiao (ORCID: https://orcid.org/0000-0002-5916-6107)
- Gayoung Seo (ORCID: https://orcid.org/0000-0002-6738-2686)
- Jeongmin An (ORCID: https://orcid.org/0000-0002-2357-0941)
- Zhipeng Meng (ORCID: https://orcid.org/0000-0003-4756-6303)
- Colette Ahn
- Han Han (ORCID: https://orcid.org/0000-0003-2222-5270)
- Yuhan Liu (ORCID: https://orcid.org/0000-0003-1990-4184)
- Wenqi Wang (ORCID: https://orcid.org/0000-0003-4053-5088)
- Yue Xu (ORCID: https://orcid.org/0000-0002-4615-5441)
- Shanshan Ren
- Jiachen Yan
- Tian Lan (ORCID: https://orcid.org/0000-0002-7698-3766)
Institutions
- University of Miami (US)
- University of California, Irvine (US)
- Southern University of Science and Technology (CN)
- Westlake University (CN)
- Wuhan University (CN)
- Irvine University (US)
- Sylvester Comprehensive Cancer Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1038/s41467-024-54480-y
- Citations
- 9
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 2.93
Funders
- American Cancer Society
- National Natural Science Foundation of China
- National Institutes of Health
- Young Scientists Fund
- National Cancer Institute
- National Institute of General Medical Sciences
- Chao Family Comprehensive Cancer Center