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Tea domain transcription factor TEAD4 mitigates TGF-β signaling and hepatocellular carcinoma progression independently of YAP
Weicheng Luo1,† , Yi Li2,† , Yi Zeng1,† , Yining Li1 , Minzhang Cheng3 , Cheng Zhang1 , Fei Li1 , Yiqing Wu1 , Chunhong Huang1 , Xiaolong Yang4 , Joachim Kremerskothen5 , Jianmin Zhang6 , Chunbo Zhang7 , Shuo Tu1 , Zhihua Li8 , Zhijun Luo9 , Zhenghong Lin10,* , Xiaohua Yan1,8,*
1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang 330031, China
2Department of Rheumatology and Clinical Immunology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China
3Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
4Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada
5Department of Nephrology, Hypertension and Rheumatology, University Hospital Münster, Münster 48149, Germany
6Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14203, USA
7School of Pharmacy, Nanchang University Jiangxi Medical College, Nanchang 330008, China
8Key Laboratory of Breast Diseases of Jiangxi Province, Nanchang People’s Hospital, Nanchang 330025, China
9Department of Pathology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang 330006, China
10School of Life Sciences, Chongqing University, Chongqing 405200, China
†These authors contributed equally to this work
*Correspondence to:Zhenghong Lin , Email:zhenghonglin@cqu.edu.cn Xiaohua Yan , Email:yanxiaohua@ncu.edu.cn
J Mol Cell Biol, Volume 15, Issue 2, February 2023, mjad010,  https://doi.org/10.1093/jmcb/mjad010
Keyword: TGF-β, TEAD4, p300, signaling regulation, transcriptional activity, hepatocellular carcinoma

Tea domain transcription factor 4 (TEAD4) plays a pivotal role in tissue development and homeostasis by interacting with Yes-associated protein (YAP) in response to Hippo signaling inactivation. TEAD4 and YAP can also cooperate with transforming growth factor-β (TGF-β)-activated Smad proteins to regulate gene transcription. Yet, it remains unclear whether TEAD4 plays a YAP-independent role in TGF-β signaling. Here, we unveil a novel tumor suppressive function of TEAD4 in liver cancer via mitigating TGF-β signaling. Ectopic TEAD4 inhibited TGF-β-induced signal transduction, Smad transcriptional activity, and target gene transcription, consequently suppressing hepatocellular carcinoma cell proliferation and migration in vitro and xenograft tumor growth in mice. Consistently, depletion of endogenous TEAD4 by siRNAs enhanced TGF-β signaling in cancer cells. Mechanistically, TEAD4 associates with receptor-regulated Smads (Smad2/3) and Smad4 in the nucleus, thereby impairing the binding of Smad2/3 to the histone acetyltransferase p300. Intriguingly, these negative effects of TEAD4 on TGF-β/Smad signaling are independent of YAP, as impairing the TEAD4–YAP interaction through point mutagenesis or depletion of YAP and/or its paralog TAZ has little effect. Together, these results unravel a novel function of TEAD4 in fine tuning TGF-β signaling and liver cancer progression in a YAP-independent manner.


Volume 15, Issue 2
February 2023