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; Jianping Jin

doi:10.1038/s41467-024-49045-y

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

Nat Commun. 2024 Jun 11;15(1):4995. doi: 10.1038/s41467-024-49045-y.

Authors

Mengjia Lin^{1

2}, Xiaoyun Zheng^{2

3}, Jianing Yan⁴, Fei Huang², Yilin Chen^{2

3}, Ran Ding^{2

3}, Jinkai Wan^{5

6}, Lei Zhang⁵, Chenliang Wang², Jinchang Pan², Xiaolei Cao^{2

3}, Kaiyi Fu², Yan Lou⁷, Xin-Hua Feng^{2

3

8}, Junfang Ji^{2

3

8}, Bin Zhao^{2

3

8}, Fei Lan^{5

6}, Li Shen^{2

9}, Xianglei He¹⁰, Yunqing Qiu^{11

12}, Jianping Jin^{13

14

15

16}

Affiliations

¹ State Key Laboratory for Diagnosis and Treatment of Infectious Disease, and National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, China.
² Life Sciences Institute, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
³ Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
⁴ Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang, China.
⁵ International Co-laboratory of Medical Epigenetics and Metabolism of Ministry of Science and Technology, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
⁶ Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, and Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
⁷ Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, Department of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, China.
⁸ Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, 321000, China.
⁹ Department of Orthopedics Surgery, School of Medicine, The Second Affiliated Hospital, Zhejiang University, Hangzhou, 310009, Zhejiang, China.
¹⁰ Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, 3100014, Zhejiang, China.
¹¹ State Key Laboratory for Diagnosis and Treatment of Infectious Disease, and National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, China. qiuyq@zju.edu.cn.
¹² Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, Department of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, China. qiuyq@zju.edu.cn.
¹³ Life Sciences Institute, Zhejiang University, Hangzhou, 310058, Zhejiang, China. jianping_jin@zju.edu.cn.
¹⁴ Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China. jianping_jin@zju.edu.cn.
¹⁵ Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, Department of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, China. jianping_jin@zju.edu.cn.
¹⁶ Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, 321000, China. jianping_jin@zju.edu.cn.

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.

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / metabolism
Carcinoma, Hepatocellular* / pathology
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation*
DNA-Binding Proteins* / genetics
DNA-Binding Proteins* / metabolism
Disease Progression
Female
Gene Expression Regulation, Neoplastic
HEK293 Cells
Hippo Signaling Pathway
Humans
Liver Neoplasms* / genetics
Liver Neoplasms* / metabolism
Liver Neoplasms* / pathology
Male
Mice
Mice, Nude
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Signal Transduction*
TEA Domain Transcription Factors* / metabolism
Transcription Factors* / genetics
Transcription Factors* / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
Ubiquitination*
YAP-Signaling Proteins* / metabolism

Substances

Transcription Factors
DNA-Binding Proteins
YAP-Signaling Proteins
TEA Domain Transcription Factors
Adaptor Proteins, Signal Transducing
YAP1 protein, human
Ubiquitin-Protein Ligases
TEAD1 protein, human
Nuclear Proteins

Abstract

MeSH terms

Substances

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