The Roles Of TEAD4 Protein In Regulating TGF-β/Smad Signaling And Liver Cancer Cell Migration And Invasion

Liver cancer is the second leading cause of cancer-related death worldwide,and hepatocellular carcinoma(HCC)is the most common type of primary liver cancers.TGF-β plays distinct roles in the early and late stages of liver cancer development,it can promote the migration and invasion of liver cancer cells.TEAD4 belongs to the TEAD transcription factor protein family,which regulate gene expression by recruiting transcriptional co-factors like YAP/TAZ.It has been demonstrated that TEADs and YAP bind to Smad proteins,yet the role and mechanism of TEAD4 in regulating TGF-β signaling and Smad-induced gene transcription need further elucidation.In this thesis,we found that overexpression of TEAD4 protein is able to inhibit TGF-β signaling,and TGF-β-induced target gene expression on a genome wide scale.TEAD4 could inhibit the transcriptional activity of Smad proteins,thereby mitigating TGF-β-elicited target gene expression.Functionally,TEAD4 inhibits TGF-β-induced cell migration,invasion and proliferation in HCC.Intriguingly,both the wild-type TEAD4 and its derivatives that lose the ability to associate with YAP,are capable of suppressing TGF-β/Smad signaling and TGF-β functions in HCC cells.Together,the above results indicate that TEAD4 protein plays an inhibitory role in TGF-β/Smad signaling in a YAP-independent manner.This regulation is of significance in modulating cancer cell functions in HCC.