Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts

Cell Death Differ. 2001 Oct;8(10):1014-21. doi: 10.1038/sj.cdd.4400914.


We recently reported that butyrate, an inhibitor of histone deacetylases, is capable of inducing Fas-independent apoptosis in the acute lymphoblastic leukemia cell line CCRF-CEM. Here we demonstrate that butyrate enhances Fas-induced apoptosis in this cell line. The application of different histone deacetylase inhibitors revealed that tetra-acetylated histone H4 is associated with the amplifying effect of butyrate on Fas-induced cell death. FasL, Fas, FADD, RIP, caspase-8, caspase-3, Bid, FLIP(S+L), FLASH and FAP-1, proteins known to act within the Fas-apoptosis cascade, showed no changes in their expression levels in cells treated with butyrate compared with untreated cells. Analyses of Fas-oligomerization and Western blotting as well as enzyme activity assays of caspase-2, caspase-3 and caspase-8 suggest that butyrate enhances Fas-induced apoptosis downstream of Fas but upstream of caspase-8 activation. In immunoprecipitation experiments a 37 kD butyrate-regulated protein was detected which specifically interacts with caspase-8.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Butyrates / pharmacology
  • Caspase 2
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Fatty Acids / pharmacology
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Kinetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology
  • fas Receptor / physiology*


  • Butyrates
  • Enzyme Inhibitors
  • Fatty Acids
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • trichostatin A
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 2
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases