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

Nuclear translocation of beta-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 beta-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 beta-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 beta-catenin. HDAC6 deacetylates beta-catenin at lysine 49, a site frequently mutated in anaplastic thyroid cancer, and inhibits beta-catenin phosphorylation at serine 45. HDAC6 inactivation blocks EGF-induced beta-catenin nuclear localization and decreases c-Myc expression, leading to inhibition of tumor cell proliferation. These results suggest that EGF-induced nuclear localization of beta-catenin is regulated by HDAC6-dependent deacetylation and provide a new mechanism by which HDAC inhibitors prevent tumor growth.

Pubmed ID: 18356165

Authors

  • Li Y
  • Zhang X
  • Polakiewicz RD
  • Yao TP
  • Comb MJ

Journal

The Journal of biological chemistry

Publication Data

May 9, 2008

Associated Grants

  • Agency: NINDS NIH HHS, Id: R01 NS054022
  • Agency: NINDS NIH HHS, Id: R01 NS054022-03

Mesh Terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cell Nucleus
  • Cell Proliferation
  • Enzyme Activation
  • Epidermal Growth Factor
  • Histone Deacetylases
  • Humans
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Sequence Alignment
  • beta Catenin