Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts.
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.
Bernhard
D
D
Tyrolean Cancer Research Institute, Innrain 66, A-6020 Innsbruck, Austria. David_Bernhard@yahoo.com
Skvortsov
S
S
Tinhofer
I
I
Hübl
H
H
Greil
R
R
Csordas
A
A
Kofler
R
R
D017209:Apoptosis; D002087:Butyrates / Q000494:pharmacology; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007700:Kinetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000473:pathology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000502:physiology*
D002087:Butyrates; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C012589:trichostatin A; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases