@article{f36ac9d134d74aec9684720cc4bac80f,
title = "Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis",
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 {\^I} {"}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.",
author = "Hutt, {Darren M.} and David Herman and Rodrigues, {Ana P.C.} and Sabrina Noel and Pilewski, {Joseph M.} and Jeanne Matteson and Ben Hoch and Wendy Kellner and Kelly, {Jeffery W.} and Andre Schmidt and Thomas, {Philip J.} and Yoshihiro Matsumura and Skach, {William R.} and Martina Gentzsch and Riordan, {John R.} and Sorscher, {Eric J.} and Tsukasa Okiyoneda and Yates, {John R.} and Lukacs, {Gergely L.} and Frizzell, {Raymond A.} and Gerard Manning and Gottesfeld, {Joel M.} and Balch, {William E.}",
note = "Funding Information: We thank J.P. Clancy (University of Alabama, Birmingham) for the CFBE41o-expressing ∆F508 and the corrected CFBE41o-(WT-HBE41o-) expressing wild-type CFTR. This work was supported by US National Institutes of Health (NIH) grants HL79442 and GM42336 and aid from the Cystic Fibrosis Consortium to W.E.B.; NIH grant NS055781 to J.M.G.; NIH grants DK68196 and DK72506 and aid from the Cystic Fibrosis Consortium to R.A.F.; NIH grant UR98647 and aid from the Cystic Fibrosis Consortium to E.J.S.; NIH grant AG03197 to J.W.K.; NIH grant DK23567 to J.R.R.; NIH grant AG78594 to G.M.; and NIH grant DK075302 and aid from the Canadian Institutes of Health Research to G.L.L. D.M.H. has received support by fellowships from the Canadian Cystic Fibrosis Foundation and the Canadian Institutes of Health Research; D.H. was supported by a fellowship from the Friedreich{\textquoteright}s Ataxia Research Alliance. T.O. was supported by a fellowship from the Canadian Cystic Fibrosis Foundation.",
year = "2010",
month = jan,
doi = "10.1038/nchembio.275",
language = "English (US)",
volume = "6",
pages = "25--33",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "1",
}