TEAD4 And VGLL4 Inhibit TGF-β Signaling In Hepatocellular Carcinoma Cells

Primary liver cancers are common malignant tumors and the second cause of cancer-related death worldwide,making them a serious threat to human health.Hepatocellular carcinoma(HCC)is the main type of primary liver cancers.TGF-β plays a dual role in the development of liver cancer.Although inhibiting the cancer cell growth in the early stage,TGF-β is transformed into a cancer-promoting factor along with HCC development,via promotion of cancer cell growth,migration and metastasis.Upon binding to the cell membrane receptors,TGF-β stimulates the phosphorylation of R-Smad(Smad2/3)proteins and association with Smad4.Then the Smad complex accumulate in the nucleus and act as transcription factors to bind DNA and regulate the transcription of target genes.In addition,Smad-mediated transcriptional regulation requires the participation of other transcription factors and cofactors,depending on cell types,extracellular signals and different physiological conditions.TEAD4 belongs to the TEAD transcription factor protein family and is the final effector downstream of the Hippo signaling pathway.TEAD4 mainly plays a transcriptional regulatory role by binding to the transcriptional coactivator YAP and TAZ.VGLL4 can compete with YAP/TAZ to bind TEAD proteins.Evidence indicates that TEADs,YAP and Smad proteins can form different protein complexes to regulate the expression of certain genes.However,it is unclear whether TEAD proteins can play a role in TGF-β signaling in the absence of YAP/TAZ.In this thesis,we found that overexpression of TEAD4 protein significantly suppressed TGF-β signaling,while si RNA-mediated depletion of TEAD4 promoted TGF-β signaling and enhanced HCC cell proliferation,migration and invasion.Mechanistic investigations revealed that TEAD4 inhibits the binding of Smad2/3 to the histone acetyltransferase p300,thereby inhibiting the transcriptional regulatory activity of Smad2/3 and weakening the expression of TGF-β target genes.Interestingly,the inhibitory effects of TEAD4 on TGF-β signal are independent of YAP/TAZ proteins.On the other hand,our preliminary data showed that TEAD4 and VGLL4 can jointly inhibit TGF-β signaling,the transcriptional activity of Smad2/3,the expression of target genes,and migration and invasion of liver cancer cells.The above results unveil novel regulatory effects of TEAD4 and VGLL4 on TGF-β signaling,which is of significance in controlling the cellular functions of liver cancer cells.