Oncotarget

Priority Research Papers:

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

Xiaolan Deng, Ryuji Hamamoto, Theodore Vougiouklakis, Rui Wang, Yuichiro Yoshioka, Takehiro Suzuki, Naoshi Dohmae, Yo Matsuo, Jae-Hyun Park and Yusuke Nakamura _

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Oncotarget. 2017; 8:55837-55847. https://doi.org/10.18632/oncotarget.19646

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Abstract

Xiaolan Deng1, Ryuji Hamamoto1, Theodore Vougiouklakis1, Rui Wang1, Yuichiro Yoshioka1, Takehiro Suzuki3, Naoshi Dohmae3, Yo Matsuo4, Jae-Hyun Park1 and Yusuke Nakamura1,2

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.


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