Dysregulation of the Hippo pathway occurs in a variety of cancers and often correlates with a poor prognosis.To further explore the potential role of Hippo pathway dysregulation in tumor development and progression,we investigated its downstream transcription factor TEAD4 in colorectal cancer(CRC).Increased expression and nuclear localization of TEAD4 were found in a significant portion of CRC tissues,in association with metastasis and a poor prognosis.In CRC cells,TEAD4 knockdown induced the mesenchymal-epithelial transition and decreased cell mobility in vitro and metastasis in vivo.Microarray analysis revealed that TEAD4 promoted cell adhesion and upregulated the EMT-related transcriptome in CRC cells.Vimentin was identified as a new direct target gene mediating TEAD4 function in CRC cells,whereby forced vimentin expression markedly reversed TEAD4 knockdown-induced cell morphological changes and decreased mobility.SIX1 was another direct target gene of TEAD4 in colorectal cancer.TEAD4 indirectly inhibited CDH1 expression through promoting SIX1 expression.Interestingly,rescued expression of both WT TEAD4 and a Y429H mutant can reverse the mesenchymalepithelial transition and increase vimentin expression,cell mobility and metastatic potential in TEAD4-knockdown CRC cells.The discrepant expression of YAP and TEAD4 in CRC tissues,the rescue ability of TEAD4 mutant defect in YAP binding and no effect on vimentin expression by YAP knockdown in CRC cells all implicated a YAP independent manner of TEAD4 function in CRC.The transcription factor TEAD4 regulates a pro-metastasis transcription program in a YAPindependent manner in CRC,thus providing a novel mechanism of TEAD4 transcriptional regulation and its oncogenic role in CRC,independently of the Hippo pathway.