MODULATION OF GROWTH AND DIFFERENTIATION OF HUMAN COLON-CARCINOMA CELLS BY HISTONE DEACETYLASE INHIBITORY TRICHOSTATINS

Histone deacetylase inhibitors such as sodium butyrate or (R)-trichost atin A {(R)-TSA; 7- [4-(dimethylamino) phenyl]-N-hydroxy-4,6-dimethyl- 7-oxo-2, 4-heptadienamide} have been reported to modulate the prolifer ation and differentiation of certain cell types. In this study, we ana lyzed the effects of these agents on KM12 human colon carcinoma (HCC) cells in culture. We found that (R)-TSA induced cell flattening, inhib ited anchorage-dependent and anchorage-independent growth, increased t he level of the differentiation marker carcinoembryonic antigen, and i ncreased the expression of gelsolin, a candidate tumor suppressor, in these HCC cells. Cells treated with (R)-TSA for 3 h exhibited a high d egree of histone (primarily H4) acetylation. (R)-TSA exerted these eff ects at concentrations in the range between 0.1 to 1 mu M that are at least 1,000 times lower than those required to achieve similar effects by n-butyrate. Trichostatin C, which exhibits some histone deacetylas e inhibitory activity but not the analogs (S)-TSA or (R)- or (S)-trich ostatic acid, which lack histone deacetylase inhibitory activity, also showed some growth inhibitory activity. These results indicate that h istone deacetylase inhibitors may lead to suppression of the transform ed phenotype and enhanced differentiation in the KM12 HCC cells.