The RNF214-TEAD-YAP signaling axis promotes hepatocellular carcinoma progression via TEAD ubiquitylation

Mengjia Lin, Xiaoyun Zheng, Jianing Yan, Fei Huang, Yilin Chen, Ran Ding, Jinkai Wan, Lei Zhang, Chenliang Wang, Jinchang Pan, Xiaolei Cao, Kaiyi Fu, Yan Lou, Xin-Hua Feng, Junfang Ji, Bin Zhao, Fei Lan, Li Shen, Xianglei He, Yunqing Qiu () and Jianping Jin ()
Additional contact information
Mengjia Lin: Zhejiang University
Xiaoyun Zheng: Zhejiang University
Jianing Yan: Zhejiang University School of Medicine
Fei Huang: Zhejiang University
Yilin Chen: Zhejiang University
Ran Ding: Zhejiang University
Jinkai Wan: Fudan University
Lei Zhang: Fudan University
Chenliang Wang: Zhejiang University
Jinchang Pan: Zhejiang University
Xiaolei Cao: Zhejiang University
Kaiyi Fu: Zhejiang University
Yan Lou: Zhejiang University
Xin-Hua Feng: Zhejiang University
Junfang Ji: Zhejiang University
Bin Zhao: Zhejiang University
Fei Lan: Fudan University
Li Shen: Zhejiang University
Xianglei He: Zhejiang Provincial People’s Hospital
Yunqing Qiu: Zhejiang University
Jianping Jin: Zhejiang University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract RNF214 is an understudied ubiquitin ligase with little knowledge of its biological functions or protein substrates. Here we show that the TEAD transcription factors in the Hippo pathway are substrates of RNF214. RNF214 induces non-proteolytic ubiquitylation at a conserved lysine residue of TEADs, enhances interactions between TEADs and YAP, and promotes transactivation of the downstream genes of the Hippo signaling. Moreover, YAP and TAZ could bind polyubiquitin chains, implying the underlying mechanisms by which RNF214 regulates the Hippo pathway. Furthermore, RNF214 is overexpressed in hepatocellular carcinoma (HCC) and inversely correlates with differentiation status and patient survival. Consistently, RNF214 promotes tumor cell proliferation, migration, and invasion, and HCC tumorigenesis in mice. Collectively, our data reveal RNF214 as a critical component in the Hippo pathway by forming a signaling axis of RNF214-TEAD-YAP and suggest that RNF214 is an oncogene of HCC and could be a potential drug target of HCC therapy.

Date: 2024
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DOI: 10.1038/s41467-024-49045-y

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