Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis

Darren M. Hutt, David Herman, Ana P C Rodrigues, Sabrina Noel, Joseph M. Pilewski, Jeanne Matteson, Ben Hoch, Wendy Kellner, Jeffery W. Kelly, Andre Schmidt, Philip J. Thomas, Yoshihiro Matsumura, William R. Skach, Martina Gentzsch, John R. Riordan, Eric J. Sorscher, Tsukasa Okiyoneda, John R. Yates, Gergely L. Lukacs, Raymond A. Frizzell & 3 others Gerard Manning, Joel M. Gottesfeld, William E. Balch

Research output: Contribution to journalArticle

175 Citations (Scopus)

Abstract

Chemical modulation of histone deacetylase (HDAC) activity by HDAC inhibitors (HDACi) is an increasingly important approach for modifying the etiology of human disease. Loss-of-function diseases arise as a consequence of protein misfolding and degradation, which lead to system failures. The Î "F508 mutation in cystic fibrosis transmembrane conductance regulator (CFTR) results in the absence of the cell surface chloride channel and a loss of airway hydration, leading to the premature lung failure and reduced lifespan responsible for cystic fibrosis. We now show that the HDACi suberoylanilide hydroxamic acid (SAHA) restores surface channel activity in human primary airway epithelia to levels that are 28% of those of wild-type CFTR. Biological silencing of all known class I and II HDACs reveals that HDAC7 plays a central role in restoration of δF508 function. We suggest that the tunable capacity of HDACs can be manipulated by chemical biology to counter the onset of cystic fibrosis and other human misfolding disorders.

Original languageEnglish (US)
Pages (from-to)25-33
Number of pages9
JournalNature Chemical Biology
Volume6
Issue number1
DOIs
StatePublished - Jan 2010

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Cystic Fibrosis Transmembrane Conductance Regulator
Histone Deacetylase Inhibitors
Histone Deacetylases
Cystic Fibrosis
Chloride Channels
Human Activities
Proteolysis
Epithelium
Lung
Mutation
vorinostat

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Hutt, D. M., Herman, D., Rodrigues, A. P. C., Noel, S., Pilewski, J. M., Matteson, J., ... Balch, W. E. (2010). Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis. Nature Chemical Biology, 6(1), 25-33. https://doi.org/10.1038/nchembio.275

Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis. / Hutt, Darren M.; Herman, David; Rodrigues, Ana P C; Noel, Sabrina; Pilewski, Joseph M.; Matteson, Jeanne; Hoch, Ben; Kellner, Wendy; Kelly, Jeffery W.; Schmidt, Andre; Thomas, Philip J.; Matsumura, Yoshihiro; Skach, William R.; Gentzsch, Martina; Riordan, John R.; Sorscher, Eric J.; Okiyoneda, Tsukasa; Yates, John R.; Lukacs, Gergely L.; Frizzell, Raymond A.; Manning, Gerard; Gottesfeld, Joel M.; Balch, William E.

In: Nature Chemical Biology, Vol. 6, No. 1, 01.2010, p. 25-33.

Research output: Contribution to journalArticle

Hutt, DM, Herman, D, Rodrigues, APC, Noel, S, Pilewski, JM, Matteson, J, Hoch, B, Kellner, W, Kelly, JW, Schmidt, A, Thomas, PJ, Matsumura, Y, Skach, WR, Gentzsch, M, Riordan, JR, Sorscher, EJ, Okiyoneda, T, Yates, JR, Lukacs, GL, Frizzell, RA, Manning, G, Gottesfeld, JM & Balch, WE 2010, 'Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis', Nature Chemical Biology, vol. 6, no. 1, pp. 25-33. https://doi.org/10.1038/nchembio.275
Hutt, Darren M. ; Herman, David ; Rodrigues, Ana P C ; Noel, Sabrina ; Pilewski, Joseph M. ; Matteson, Jeanne ; Hoch, Ben ; Kellner, Wendy ; Kelly, Jeffery W. ; Schmidt, Andre ; Thomas, Philip J. ; Matsumura, Yoshihiro ; Skach, William R. ; Gentzsch, Martina ; Riordan, John R. ; Sorscher, Eric J. ; Okiyoneda, Tsukasa ; Yates, John R. ; Lukacs, Gergely L. ; Frizzell, Raymond A. ; Manning, Gerard ; Gottesfeld, Joel M. ; Balch, William E. / Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis. In: Nature Chemical Biology. 2010 ; Vol. 6, No. 1. pp. 25-33.
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