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J. Biol. Chem., Vol. 283, Issue 19, 12686-12690, May 9, 2008

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HDAC6 Is Required for Epidermal Growth Factor-induced β-Catenin Nuclear Localization^*

Yu Li, Xiaowu Zhang, Roberto D. Polakiewicz, Tso-Pang Yao, and Michael J. Comb¹

From the Cell Signaling Technology, Danvers, Massachusetts 01923 and the Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710

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.

Received for publication, September 24, 2007 , and in revised form, March 20, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Cell Signaling Technology; 3 Trask La., Danvers, MA 01923. Tel.: 978-867-2315; Fax: 978-867-2300; E-mail: mcomb{at}cellsignal.com.