TRICHOSTATIN-A INDUCES MORPHOLOGICAL-CHANGES AND GELSOLIN EXPRESSION BY INHIBITING HISTONE DEACETYLASE IN HUMAN CARCINOMA CELL

Trichostatin A (TSA) is a Streptomyces metabolite which specifically i nhibits mammalian histone deacetylase at a nanomolar concentration and causes accumulation of highly acetylated histone molecules in mammali an cells. The effects of TSA on the morphology and the cell cycle of t he human carcinoma cell lines, T24 and HeLa, were investigated. The mo rphology of T24 and HeLa cells dramatically changed and actin stress f ibers reappeared during the treatment with TSA. The morphological chan ge was not observed with chemically synthesized (S)-TSA and trichostat ic acids, which are inactive to inhibit histone deacetylase. Cell cycl e progression of these cells was blocked by TSA at G1 phase (HeLa) or G1 and G2 phases (T24). An RNA synthesis inhibitor, actinomycin D, and a protein synthesis inhibitor, cycloheximide, inhibited the morpholog ical changes by TSA, suggesting that TSA induces expression of a new g ene(s) followed by de novo protein synthesis, which is required for th e actin microfilament reorganization. An approximately 7-fold (T24) or 12-fold (HeLa) increase in the intracellular level of gelsolin, an ac tin regulatory protein, was found in the cells treated with TSA for 24 h. These results suggest that gelsolin is one of the putative protein s necessary for the morphological changes of human carcinoma cells ind uced by TSA. (C) 1994 Academic Press, Inc.