Our results show through epistasis experiments that piperine inhibits Wnt signaling activated by constitutively activate form of TCF (dnTCF4 VP16) and also inhibits β-catenin nuclear localization in HCT116, a colorectal cancer cell line that harbors a mutated β-catenin form that overactivates Wnt signaling. Here, HNF4A is linked to colorectal cancer.