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

// Xiaolan Deng 1 , Ryuji Hamamoto 1 , Theodore Vougiouklakis 1 , Rui Wang 1 , Yuichiro Yoshioka 1 , Takehiro Suzuki 3 , Naoshi Dohmae 3 , Yo Matsuo 4 , Jae-Hyun Park 1 and Yusuke Nakamura 1,2 1 Department of Medicine, The University of Chicago, Chicago, IL, USA 2 Department of Surgery, The University of Chicago, Chicago, IL, USA 3 Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan 4 OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan Correspondence to: Yusuke Nakamura, email: // Keywords : β-catenin, Wnt signaling pathway, SMYD2, lysine methylation Received : June 30, 2017 Accepted : July 06, 2017 Published : July 27, 2017 Abstract Accumulation of β-catenin in the nucleus is a hallmark of activation of the Wnt/β-catenin signaling pathway, which drives development of a large proportion of human cancers. However, the mechanism of β-catenin nuclear translocation has not been well investigated. Here we report biological significance of SMYD2-mediated lysine 133 (K133) methylation of β-catenin on its nuclear translocation. Knockdown of SMYD2 attenuates the­­­­­­ nuclear localization of β-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 β-catenin almost completely abolishes its nuclear localization. We also demonstrate the K133 methylation is critical for the interaction of β-catenin with FOXM1. Furthermore, after treatment with a SMYD2 inhibitor, significant reduction of nuclear β-catenin and subsequent induction of cancer cell death are observed. Accordingly, our results imply that β-catenin methylation by SMYD2 promotes its nuclear translocation and activation of Wnt signaling.