Targeted degradation of endogenous YAP by nanobody bioPROTAC inhibits tumor progression

Yes-associated protein (YAP), a key effector of the Hippo pathway, regulates gene expression and promotes tumorigenesis. YAP is conventionally considered "undruggable", however, targeted protein degradation offers a promising approach to address the challenges associated with targeting this oncogenic protein. In this study, through naïve nanobody phage library screening, we identify multiple nanobodies against human YAP with high affinity and specificity. The YAP nanobody is then fused to the RING domain of RNF4, creating a bio-Proteolysis-Targeting Chimera (bioPROTAC) molecule capable of selectively targeting endogenous YAP for ubiquitin-mediated degradation. Notably, the constructed YAP bioPROTAC demonstrates significant YAP degradation and anticancer efficacy in various YAP-dependent cancers both in vitro and in vivo. Nanoparticles and adeno-associated virus (AAV) can effectively deliver the encoding gene of YAP bioPROTAC, achieving YAP degradation in tumors. Collectively, our study provides a proof-of-concept that the YAP nanobody-bioPROTAC approach can effectively degrade endogenous YAP via the ubiquitin-proteasome system, highlighting a feasible strategy for "undruggable" YAP-dependent cancers.

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Publication Details

Journal
Nature Communications
Published
2025-10-23
DOI
https://doi.org/10.1038/s41467-025-64426-7
Citations
4
Primary Topic
Hippo pathway signaling and YAP/TAZ
Type
article
Field-Weighted Citation Impact
4.61

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article

Targeted degradation of endogenous YAP by nanobody bioPROTAC inhibits tumor progression

Guangwei Shi, Y Q Li, Chengming Qu, Jiuhong Yuan et al.
4 citations
Nature Communications
Hippo pathway signaling and YAP/TAZ
4.61
article

Targeted degradation of endogenous YAP by nanobody bioPROTAC inhibits tumor progression

Guangwei Shi, Y Q Li, Chengming Qu, Jiuhong Yuan, Jingnan Huang, Liang Chen, Zhijie Li, Jigang Wang, Lingyun Dai, Yang Li, Le Yu, Xiaolian Liu, Yawei Liu, Huifang Wang, Guiming Zhang, Hongchao Zhou, Chongzhi Bai, Zhifen Li, Runhua Zhou
article en
4 citations

Abstract

Yes-associated protein (YAP), a key effector of the Hippo pathway, regulates gene expression and promotes tumorigenesis. YAP is conventionally considered "undruggable", however, targeted protein degradation offers a promising approach to address the challenges associated with targeting this oncogenic protein. In this study, through naïve nanobody phage library screening, we identify multiple nanobodies against human YAP with high affinity and specificity. The YAP nanobody is then fused to the RING domain of RNF4, creating a bio-Proteolysis-Targeting Chimera (bioPROTAC) molecule capable of selectively targeting endogenous YAP for ubiquitin-mediated degradation. Notably, the constructed YAP bioPROTAC demonstrates significant YAP degradation and anticancer efficacy in various YAP-dependent cancers both in vitro and in vivo. Nanoparticles and adeno-associated virus (AAV) can effectively deliver the encoding gene of YAP bioPROTAC, achieving YAP degradation in tumors. Collectively, our study provides a proof-of-concept that the YAP nanobody-bioPROTAC approach can effectively degrade endogenous YAP via the ubiquitin-proteasome system, highlighting a feasible strategy for "undruggable" YAP-dependent cancers.

Nature CommunicationsVol. 16(1)
Guangdong Pharmaceutical University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Southern University of Science and Technology (CN), Wuhan University (CN), The First People's Hospital of Shunde (CN), Shanxi Province Hospital of Traditional Chinese Medicine (CN), Zhongnan Hospital of Wuhan University (CN), China Academy of Chinese Medical Sciences (CN), Southern Medical University Shenzhen Hospital (CN), Shenzhen Second People's Hospital (CN), Shanxi Datong University (CN), Southern Medical University (CN)
National Natural Science Foundation of China, Shenzhen Municipal Science and Technology Innovation Council, Wu Jieping Medical Foundation, Basic and Applied Basic Research Foundation of Guangdong Province
Openalex Percentile: Top 5%
Hippo pathway signaling and YAP/TAZ
4.61
DOIOpen Access PDFOpenAlex
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