Critical roles of SMYD2-mediated β-catenin methylation for nuclear translocation and activation of Wnt signaling

Accumulation of beta-catenin in the nucleus is a hallmark of activation of the Wnt/beta-catenin signaling pathway, which drives development of a large proportion of human cancers. However, the mechanism of beta-catenin nuclear translocation has not been well investigated. Here we report biological significance of SMYD2-mediated lysine 133 (K133) methylation of beta-catenin on its nuclear translocation. Knockdown of SMYD2 attenuates the nuclear localization of beta-catenin protein in human cancer cells. Consequently, transcriptional levels of well-known Wnt-signaling molecules, cMYC and CCND1, are significantly reduced. Substitution of lysine 133 to alanine in beta-catenin almost completely abolishes its nuclear localization. We also demonstrate the K133 methylation is critical for the interaction of beta-catenin with FOXM1. Furthermore, after treatment with a SMYD2 inhibitor, significant reduction of nuclear beta-catenin and subsequent induction of cancer cell death are observed. Accordingly, our results imply that beta-catenin methylation by SMYD2 promotes its nuclear translocation and activation of Wnt signaling.