Y. Koyama et al., Histone deacetylase inhibitors suppress IL-2-mediated gene expression prior to induction of apoptosis, BLOOD, 96(4), 2000, pp. 1490-1495
Histone deacetylase (HDAC) inhibitors can induce transcriptional activation
of a number of genes and induce cellular differentiation as histone acetyl
ation levels increase. Although these inhibitors induce apoptosis in severa
l cell lines, the precise mechanism by which they do so remains obscure. Th
is study shows that HDAC inhibitors, sodium butyrate and trichostatin A (TS
A), abrogate interleukin (IL)-2-mediated gene expression in IL-2-dependent
cells. The HDAC inhibitors readily induced apoptosis in IL-2-dependent ILT-
Mat cells and BAF-B03 transfectants expressing the IL-2 receptor beta c cha
in, whereas they induced far less apoptosis in cytokine-independent K562 ce
lls. However, these inhibitors similarly increased acetylation levels of hi
stones in both cells. Although histone hyperacetylation is believed to lead
to transcriptional activation, the results showed an abrogation of IL-2-me
diated induction of c-myc, bag-1, and LC-PTP gene expression. This observed
abrogation of gene expression occurred prior to phosphatidylserine externa
lization, a process that occurs in early apoptotic cells. Considering the b
iologic role played by IL-2-mediated gene expression in cell survival, thes
e data suggest that its abrogation may contribute to the apoptotic process
induced by HDAC inhibitors. (Blood. 2000;96:1490-1495) (C) 2000 by The Amer
ican Society of Hematology.