HDAC6 is required for epidermal growth factor-induced β-catenin nuclear localization

Abstract

Nuclear translocation of β-catenin is a hallmark of Wnt signaling and is associated with various cancers. In addition to the canonical Wnt pathway activated by Wnt ligands, growth factors such as epidermal growth factor (EGF) also induce β-catenin dissociation from the adherens junction complex, translocation into the nucleus, and activation of target genes such as c-myc. Here we report that EGF-induced β-catenin nuclear localization and activation of c-myc are dependent on the deacetylase HDAC6. We show that EGF induces HDAC6 translocation to the caveolae membrane and association with β-catenin. HDAC6 deacetylates β-catenin at lysine 49, a site frequently mutated in anaplastic thyroid cancer, and inhibits β-catenin phosphorylation at serine 45. HDAC6 inactivation blocks EGF-induced β-catenin nuclear localization and decreases c-Myc expression, leading to inhibition of tumor cell proliferation. These results suggest that EGF-induced nuclear localization of β-catenin is regulated by HDAC6-dependent deacetylation and provide a new mechanism by which HDAC inhibitors prevent tumor growth. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.