TRAPOXIN, AN ANTITUMOR CYCLIC TETRAPEPTIDE, IS AN IRREVERSIBLE INHIBITOR OF MAMMALIAN HISTONE DEACETYLASE

Trapoxin yl-L-phenylalanyl-D-pipecolinyl-L-2-amino-8-oxo-9, 10-epoxy-d ecanoyl)) is a fungal product that induces morphological reversion fro m transformed to normal in sis-transformed NIH3T3 fibroblasts. Trapoxi n was found to cause accumulation of highly acetylated core histones i n a variety of mammalian cell lines. In vitro experiments using partia lly purified mouse histone deacetylase showed that a low concentration of trapoxin irreversibly inhibited deacetylation of acetylated histon e molecules. Chemical reduction of an epoxide group in trapoxin comple tely abolished the inhibitory activity, suggesting that trapoxin binds covalently to the histone deacetylase via the epoxide. In contrast, i nhibition by trichostatin A, a known potent inhibitor of histone deace tylase, was reversible. Despite the different mode of inhibition, trap oxin and trichostatin A induced almost the same biological effects on the cell cycle and differentiation. These results strongly suggest tha t the in vivo effects commonly induced by these agents can be attribut ed to histone hyperacetylation resulting from the inhibition of histon e deacetylase.