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J Biol Chem. 2008 Jul 25;283(30):21065-73. doi: 10.1074/jbc.M802786200. Epub 2008 May 21.

Requirement of HDAC6 for transforming growth factor-beta1-induced epithelial-mesenchymal transition.

Author information

1
Department of Medicine and Tulane Cancer Center, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA. bshan@tulane.edu

Abstract

The aberrant expression of transforming growth factor (TGF)-beta1 in the tumor microenvironment and fibrotic lesions plays a critical role in tumor progression and tissue fibrosis by inducing epithelial-mesenchymal transition (EMT). EMT promotes tumor cell motility and invasiveness. How EMT affects motility and invasion is not well understood. Here we report that HDAC6 is a novel modulator of TGF-beta1-induced EMT. HDAC6 is a microtubule-associated deacetylase that predominantly deacetylates nonhistone proteins, including alpha-tubulin, and regulates cell motility. We showed that TGF-beta1-induced EMT is accompanied by HDAC6-dependent deacetylation of alpha-tubulin. Importantly, inhibition of HDAC6 by small interfering RNA or the small molecule inhibitor tubacin attenuated the TGF-beta1-induced EMT markers, such as the aberrant expression of epithelial and mesenchymal peptides, as well as the formation of stress fibers. Reduced expression of HDAC6 also impaired the activation of SMAD3 in response to TGF-beta1. Conversely, inhibition of SMAD3 activation substantially impaired HDAC6-dependent deacetylation of alpha-tubulin as well as the expression of EMT markers. These findings reveal a novel function of HDAC6 in EMT by intercepting the TGF-beta-SMAD3 signaling cascade. Our results identify HDAC6 as a critical regulator of EMT and a potential therapeutic target against pathological EMT, a key event for tumor progression and fibrogenesis.

PMID:
18499657
PMCID:
PMC2475688
DOI:
10.1074/jbc.M802786200
[Indexed for MEDLINE]
Free PMC Article

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