Down-regulation of HDAC3 inhibits growth of cholangiocarcinoma by inducing apoptosis

Class I histone deacetylases (HDACs) inhibit expression of tumor suppressor genes by removing acetyl groups from histone lysine residues, thereby increasing cancer cell survival and proliferation. We evaluated the expression of class I HDACs in cholangiocarcinoma (CCA). HDAC3 expression was specifically increased in CCA tissues and correlated with reduced patient survival. HDAC3 overexpression inhibited apoptosis and promoted CCA cell proliferation. Conversely, HDAC3 knockdown or pharmacological inhibition decreased CCA cell growth and increased caspase-dependent apoptosis. Inhibition of class I HDACs blocked HDAC3-catalyzed deacetylation and increased expression of downstream pro-apoptotic targets in vitro and in vivo. These results demonstrate for the first time that down-regulation of HDAC3 induces apoptosis in human CCA cells, indicating that inhibiting HDAC3 may be an effective therapeutic strategy for treating CCA.