FR901228, A POTENT ANTITUMOR ANTIBIOTIC, IS A NOVEL HISTONE DEACETYLASE INHIBITOR

Screening for microbial metabolites that induce transcriptional activa tion of the SV40 promoter resulted in the identification of two known compounds, FR901228 and trichostatin A (TSA), FR901228 is a potent ant itumor drug that is currently under clinical investigation. TSA is a s pecific inhibitor of histone deacetylase. Despite structural unrelated ness, both FR901228 and TSA greatly enhanced the transcriptional activ ity of the SV IO promoter in an enhancer-dependent manner. The effects of FR901228 on the cell cycle, chromatin structure, and histone acety lation were examined and compared with those of TSA. Both compounds ca used arrest of the cell cycle at both G(1) and G(2)/M phases and induc tion of internucleosomal breakdown of chromatin. FR901228, like TSA, i nhibited intracellular histone deacetylase activity, as a result of wh ich marked amounts of acetylated histone species accumulated, FR901228 is therefore a new type of histone deacetylase inhibitor, whose chemi cal structure is unrelated to known inhibitors such as trichostatins a nd trapoxins. (C) 1998 Academic Press.