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

We recently reported that butyrate, an inhibitor of histone deacetylases, i s 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 associa ted with the amplifying effect of butyrate on Fas-induced cell death. FasL, Fas, FADD, RIP, caspase-8, caspase-3, Bid, FLIPS+L, FLASH and FAP-1, prote ins known to act within the Fas-apoptosis cascade, showed no changes in the ir expression levels in cells treated with butyrate compared with untreated cells. Analyses of Fas-oligomerization and Western blotting as well as enz yme activity assays of caspase-2, caspase-3 and caspase-8 suggest that buty rate enhances Fas-induced apoptosis downstream of Fas but upstream of caspa se-8 activation. In immunoprecipitation experiments a 37 kD butyrate-regula ted protein was detected which specifically interacts with caspase-8.