Bcl-2 related proteins are dramatically induced at the early stage of differentiation in human liver cancer cells by a histone deacetylase inhibitor projecting an anti-apoptotic role during this period

Expression of the Bcl-2 family members in a human hepatocellular carcinoma cell line (HCC-T) after sodium butyrate-treatment was investigated. Sodium butyrate, a histone deacetylase inhibitor, induced differentiation of the cell line into its normal counterpart without inducing apoptosis at the concentration of 2 mmol/l. Since sodium butyrate has effects on both differentiation and apoptosis, we investigated the expression profile of bcl-2 related genes in HCC-T. The expression of Bcl-2 and Mcl-1/EAT was up-regulated 4-12 h after the treatment while Bcl-X-L was up-regulated 2-3 days after the stimulation. On the other hand, the expression levels of Bax protein remained unchanged during differentiation. The HCC-T cells entered a cell cycle arrest at G(1) and showed neither cellular fragmentation nor apoptosis during this period, which was concomitantly associated with up-regulated expression of a cell cycle regulator, p21(WAF-1). These results demonstrate that induction of anti-apoptotic Bcl-2 related proteins at an early stage of differentiation is important for maintenance of the HCC-T cell differentiation by antagonizing pro-apoptotic molecules such as Bax.