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 DeltaF508 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 DeltaF508 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.
authors: Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA.
authors: Darren M
authors: DM
authors: Hutt
authors: David
authors: D
authors: Herman
authors: Ana P C
authors: AP
authors: Rodrigues
authors: Sabrina
authors: S
authors: Noel
authors: Joseph M
authors: JM
authors: Pilewski
authors: Jeanne
authors: J
authors: Matteson
authors: Ben
authors: B
authors: Hoch
authors: Wendy
authors: W
authors: Kellner
authors: Jeffery W
authors: JW
authors: Kelly
authors: Andre
authors: A
authors: Schmidt
authors: Philip J
authors: PJ
authors: Thomas
authors: Yoshihiro
authors: Y
authors: Matsumura
authors: William R
authors: WR
authors: Skach
authors: Martina
authors: M
authors: Gentzsch
authors: John R
authors: JR
authors: Riordan
authors: Eric J
authors: EJ
authors: Sorscher
authors: Tsukasa
authors: T
authors: Okiyoneda
authors: John R
authors: JR
authors: Yates
authors: Gergely L
authors: GL
authors: Lukacs
authors: Raymond A
authors: RA
authors: Frizzell
authors: Gerard
authors: G
authors: Manning
authors: Joel M
authors: JM
authors: Gottesfeld
authors: William E
authors: WE
authors: Balch
mesh_terms: D000818:Animals; D001980:Bronchi / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D009154:Mutation; D011489:Protein Denaturation; D017510:Protein Folding; D034741:RNA, Small Interfering / Q000378:metabolism; D000077337:Vorinostat
chemical_list: C505032:CFTR protein, human; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000077337:Vorinostat; C543273:HDAC7 protein, human; D006655:Histone Deacetylases