OBJECTIVE Colorectal cancer is one of the major cause of tumor death all over the world. TEAD4 is the key factor in the YAP/TAZ signal path. This study aimed to investigate the effect and mechanism of knockdown TEAD4 for colorectal cancer cells proliferation.METHODS Transient transfection and lentivirus system are used to achieve transient or stable knockdown TEAD4 cells of Caco2 and HT-29. Western Blot is employed to detect transfection efficiency and related protein expression. SRB method and EDU Imaging Kits are used to determine cell viability and DNA synthesis.RESULTS Western blot showed knockdown of transcriptional factor TEAD4 could increase the expression of cell cycle protein p27 in Caco2 (F=45.78,P<0.001) and HT-29 (F=40.71,P<0.001) cells. SRB assays showed after using TEAD4sh#2 & TEADsh#3 to stabilize silencing TEAD4 expression in Caco2 and HT-29 cells, compared with the control group, the cell viability of TEAD4 knockdown cells Caco2(F=142.9,P<0.001) and HT-29(F=141.0,P<0.001) were significantly decreased at 2 days. The inhibition effect was more obvious, and the growth rate of Caco2(F=394.5,P<0.001) and HT-29(F=305.1,P<0.001) were significantly slower in 3 days. EdU assay demonstrated after knockdown TEAD4si#2 and TEAD4si#3 in Caco2 and HT-29 cells, DNA synthesis were (43.20±2.18)%, (27.19±2.34)%, (30.14±1.02)% and (28.23±3.11)%, (11.89±1.20)%, (17.91±2.23)%. Compared with control group, DNA synthesis was significantly inhibited in Caco2(Psi#2=0.001,Psi#3P<0.001) and HT-29 cells (Psi#2=0.001,Psi#3=0.011).CONCLUSION This study demonstrated that TEAD4 plays an important role in colorectal cancer Caco2 and HT-29 cells proliferation, partially through up-regulating p27, suggesting that TEAD4 is a potential target and biomarker for the development of novel therapeutics for colorectal cancer. © 2017, Editorial Board of Chinese Journal of Cancer Prevention and Treatment. All right reserved.