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

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

SUBMITTER: Deng X 

PROVIDER: S-EPMC5593527 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature