Tea Domain Transcriptional Factor 4 (TEAD4) mitigates TGF-β signaling and hepatocellular carcinoma progression independently of YAP.

Tea domain transcriptional factor 4 (TEAD4) plays a pivotal role in tissue development and homeostasis by interacting with YAP in response to Hippo signaling inactivation. TEAD4 and YAP can also cooperate with TGF-β-activated Smad proteins to regulate gene transcription. Yet, it remains unclear whether TEAD4 might play a YAP-independent role in TGF-β signaling. Here, we unveil a novel tumor suppressive function of TEAD4 in liver cancer via mitigation of TGF-β signaling. Ectopic TEAD4 inhibited TGF-β-induced signal transduction, Smads transcriptional activity, and their target gene transcription, consequently suppressing hepatocellular carcinoma (HCC) 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 R-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 by siRNAs has little effect. Together, these results unravel a novel function of TEAD4 in fine tuning of TGF-β signaling and liver cancer progression in a YAP-independent manner.