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

Nat Chem Biol. 2010 Jan;6(1):25-33. doi: 10.1038/nchembio.275. Epub 2009 Dec 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchi / metabolism
  • Cell Membrane / metabolism
  • Cricetinae
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Epithelial Cells / metabolism
  • Gene Silencing
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydroxamic Acids / chemistry
  • Mutation*
  • Protein Denaturation
  • Protein Folding
  • RNA, Small Interfering / metabolism
  • Vorinostat

Substances

  • CFTR protein, human
  • Hydroxamic Acids
  • RNA, Small Interfering
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Vorinostat
  • HDAC7 protein, human
  • Histone Deacetylases

Associated data

  • PubChem-Substance/85736421
  • PubChem-Substance/85736422
  • PubChem-Substance/85736423
  • PubChem-Substance/85736424
  • PubChem-Substance/85736425
  • PubChem-Substance/85736426
  • PubChem-Substance/85736427
  • PubChem-Substance/85736428
  • PubChem-Substance/85736429
  • PubChem-Substance/85736430
  • PubChem-Substance/85736431
  • PubChem-Substance/85736432