Requirement of HDAC6 for Transforming Growth Factor-beta1-induced Epithelial-mesenchymal Transition

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2008 May 24

PMID 18499657

Citations 96

Authors

Bin Shan

Tso-Pang Yao

Hong T Nguyen

Ying Zhuo

Dawn R Levy

Ross C Klingsberg

Hui Tao

Michael L Palmer

Kevin N Holder

Joseph A Lasky

Affiliations

Soon will be listed here.

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.

Citing Articles

WT161, a selective HDAC6 inhibitor, decreases growth, enhances chemosensitivity, promotes apoptosis, and suppresses motility of melanoma cells.

Oliveira-Silva J, Oliveira L, Chiminazo C, Fonseca R, Souza C, Aissa A Cancer Chemother Pharmacol. 2025; 95(1):22.

PMID: 39821335 DOI: 10.1007/s00280-024-04731-y.

Cigarette Smoke-Induced Epithelial-to-Mesenchymal Transition: Insights into Cellular Mechanisms and Signaling Pathways.

Alqithami S, Machwe A, Orren D Cells. 2024; 13(17.

PMID: 39273025 PMC: 11394110. DOI: 10.3390/cells13171453.

Histone deacetylases: potential therapeutic targets for idiopathic pulmonary fibrosis.

Cheng H, Jiang S, Cai J, Luo Z, Li X, Feng D Front Cell Dev Biol. 2024; 12:1426508.

PMID: 39193364 PMC: 11347278. DOI: 10.3389/fcell.2024.1426508.

CYLD/HDAC6 signaling regulates the interplay between epithelial-mesenchymal transition and ciliary homeostasis during pulmonary fibrosis.

Ni H, Chen M, Dong D, Zhou Y, Cao Y, Ge R Cell Death Dis. 2024; 15(8):581.

PMID: 39122680 PMC: 11316090. DOI: 10.1038/s41419-024-06972-4.

Epigenetic Regulation of EMP/EMT-Dependent Fibrosis.

Sisto M, Lisi S Int J Mol Sci. 2024; 25(5).

PMID: 38474021 PMC: 10931844. DOI: 10.3390/ijms25052775.

References

Jian H, Shen X, Liu I, Semenov M, He X, Wang X . Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev. 2006; 20(6):666-74. PMC: 1413283. DOI: 10.1101/gad.1388806. View

Zhu S, Wang W, Clarke D, Liu X . Activation of Mps1 promotes transforming growth factor-beta-independent Smad signaling. J Biol Chem. 2007; 282(25):18327-18338. DOI: 10.1074/jbc.M700636200. View

Shan B, Morris G . Binding sequence-dependent regulation of the human proliferating cell nuclear antigen promoter by p53. Exp Cell Res. 2005; 305(1):10-22. DOI: 10.1016/j.yexcr.2004.09.033. View

Kasai H, Allen J, Mason R, Kamimura T, Zhang Z . TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res. 2005; 6:56. PMC: 1177991. DOI: 10.1186/1465-9921-6-56. View

Haggarty S, Koeller K, Wong J, Grozinger C, Schreiber S . Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci U S A. 2003; 100(8):4389-94. PMC: 153564. DOI: 10.1073/pnas.0430973100. View

Murphy P, Morishima Y, Kovacs J, Yao T, Pratt W . Regulation of the dynamics of hsp90 action on the glucocorticoid receptor by acetylation/deacetylation of the chaperone. J Biol Chem. 2005; 280(40):33792-9. DOI: 10.1074/jbc.M506997200. View

North B, Marshall B, Borra M, Denu J, Verdin E . The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003; 11(2):437-44. DOI: 10.1016/s1097-2765(03)00038-8. View

Pugacheva E, Jablonski S, Hartman T, Henske E, Golemis E . HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell. 2007; 129(7):1351-63. PMC: 2504417. DOI: 10.1016/j.cell.2007.04.035. View

Dong C, Li Z, Alvarez Jr R, Feng X, Goldschmidt-Clermont P . Microtubule binding to Smads may regulate TGF beta activity. Mol Cell. 2000; 5(1):27-34. DOI: 10.1016/s1097-2765(00)80400-1. View

10.

Kalluri R, Neilson E . Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest. 2003; 112(12):1776-84. PMC: 297008. DOI: 10.1172/JCI20530. View

11.

Kim K, Kugler M, Wolters P, Robillard L, Galvez M, Brumwell A . Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A. 2006; 103(35):13180-5. PMC: 1551904. DOI: 10.1073/pnas.0605669103. View

12.

Zavadil J, Bottinger E . TGF-beta and epithelial-to-mesenchymal transitions. Oncogene. 2005; 24(37):5764-74. DOI: 10.1038/sj.onc.1208927. View

13.

Hook S, Orian A, Cowley S, Eisenman R . Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes. Proc Natl Acad Sci U S A. 2002; 99(21):13425-30. PMC: 129689. DOI: 10.1073/pnas.172511699. View

14.

Shan B, Zhuo Y, Chin D, Morris C, Morris G, Lasky J . Cyclin-dependent kinase 9 is required for tumor necrosis factor-alpha-stimulated matrix metalloproteinase-9 expression in human lung adenocarcinoma cells. J Biol Chem. 2004; 280(2):1103-11. DOI: 10.1074/jbc.M406293200. View

15.

Kovacs J, Murphy P, Gaillard S, Zhao X, Wu J, Nicchitta C . HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell. 2005; 18(5):601-7. DOI: 10.1016/j.molcel.2005.04.021. View

16.

Jinnin M, Ihn H, Tamaki K . Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-beta1-induced extracellular matrix expression. Mol Pharmacol. 2005; 69(2):597-607. DOI: 10.1124/mol.105.017483. View

17.

Thiery J, Sleeman J . Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006; 7(2):131-42. DOI: 10.1038/nrm1835. View

18.

Verdel A, Curtet S, Lemercier C, Garin J, Rousseaux S, Khochbin S . Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways. Mol Cell Biol. 2001; 21(23):8035-44. PMC: 99970. DOI: 10.1128/MCB.21.23.8035-8044.2001. View

19.

Yang J, Liu Y . Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol. 2001; 159(4):1465-75. PMC: 1850509. DOI: 10.1016/S0002-9440(10)62533-3. View

20.

Kawaguchi Y, Kovacs J, McLaurin A, Vance J, Ito A, Yao T . The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell. 2003; 115(6):727-38. DOI: 10.1016/s0092-8674(03)00939-5. View