Tea domain transcription factor TEAD4 mitigatesTGF-β signaling and hepatocellular carcinomaprogression independently of YAP

Tea domain transcription factor 4 (TEAD4) plays a pivotal role in tissue development and homeostasis by interacting with Yesassociated protein (YAP) in response to Hippo signaling inactivation. TEAD4 and YAP can also cooperate with transforminggrowth factor-β (TGF-β)-activated Smad proteins to regulate gene transcription. Yet, it remains unclear whether TEAD4 playsa YAP-independent role in TGF-β signaling. Here, we unveil a novel tumor suppressive function of TEAD4 in liver cancer viamitigating TGF-β signaling. Ectopic TEAD4 inhibited TGF-β-induced signal transduction, Smad transcriptional activity, and targetgene transcription, consequently suppressing hepatocellular carcinoma cell proliferation and migration in vitro and xenografttumorgrowth 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 Smad2/3to the histone acetyltransferase p300. Intriguingly, these negative effects of TEAD4 on TGF-β/Smad signaling are independent ofYAP, 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 YAPindependent manner.