The potassium channel KCNQ1 has been recently identified as a tumor supressor in mouse and human colorectal cancer (CRC) tissues and as a β-catenin chaperone at the plasma membrane [1,2]. The transcriptional factor 4 TCF4 forms a complex with its transcriptional coactivator beta-catenin and plays important roles in carcinogenesis of colon epithelium [2,3]. We have investigated the role of KCNQ1 association with the β-catenin:TCF4 complex in colon epitelial cancer cell lines to get an insight into their contribution to the phenotype of tumour cells. We detected KCNQ1, E-Cadherin and N-Cadherin proteins using Western blotting. Beta-catenin and KCNQ1 immunostaining was used to determine their protein localisation. Beta-catenin:TCF4 complex and KCNQ1 asociations were tested using pharmacological agents, and by KCNQ1 siRNA (SiQ1) and dominant negative TCF4 plasmid transfection (DNTCF4). Values are means ± S.E.M., compared by ANOVA. In a human CRC patient database (n=290), the Kaplan relapse-free survival data showed that KCNQ1 expression was correlated with a better survival and that there was an inverse correlation between the expression of KCNQ1 and CTNNB1 (beta-catenin) genes. We observed that KCNQ1 was highly expressed in well-differentiated CRC cell lines and this was associated with a high expression of E-cadherin and a low expression of N-cadherin. Two inhibitors of Glycogen Synthase Kinase 3-Beta (GSK3- β), AR-A014 and GSK-3iX, were used to activate beta-catenin in well-diferentiated CRC cell lines. These inhibitors produced a reduction in KCNQ1 protein expression in HT29 cells (AR-A014: 52.91±7.3, n=5 p<0.05; GSK-3iX: 55.8±10.58, n=4, p<0.05) and in Cl19A cells (AR-A014: 52.07±7.8, n=5 p<0.01; GSK-3iX: 41.8±9, n=4, p<0.01); also caused a reduction in the KCNQ1 staining intensity and in the beta-catenin nuclear localisation. The KCNQ1 expression was restored in the intermediate CRC differentiated DLD-1 cell line transfected with DNTCF4 plasmid (555±94, n=3, p<0.001). In Cl19A cells, the wound closure rate was decreased after using GSK-3iX treatment and the N-cadherin expression was increased after 24h and 48h of injury (n=3). In DLD-1 cells transfected with DNTCF4 plasmid, we observed an enhanced KCNQ1 expression (321±14 n=3, p<0.005) and an increased rate of wound closure 24h and 48h after injury. SiQ1 transfection and KCNQ1 pharmacological inhibition using HMR and C293B resulted in beta-catenin accumulation in the cytosol and a reduction in the rate of wound closure 24h after injury. In conclusion, the β-catenin:TCF4 complex represses KCNQ1 expression in colonic CRC cell lines. The expression as well as the function of KCNQ1 are directly associated with CRC patient survival, wound repair and cell differentiation processes. Our results indicate KCNQ1 as a promising new therapeutic target for the treatment of colorectal cancer.