Abstract
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 .
Highlights
Cholangiocarcinoma (CCA) is a highly malignant adenocarcinoma of mostly unknown etiology, with increasing mortality in many countries [1,2,3]
Using immunohistochemistry (IHC), we found that there was no difference in the expression of HDAC1, HDAC2, or HDAC8 isoenzymes between CCA tissues and their adjacent tissues (Figure 1A & 1B)
When we assessed the expression of HDAC3, we found that it was significantly increased in CCA tissues compared to adjacent tissues (Figure 1A & 1B)
Summary
Cholangiocarcinoma (CCA) is a highly malignant adenocarcinoma of mostly unknown etiology, with increasing mortality in many countries [1,2,3]. Epigenetic changes, including histone modifications, play an important role in malignant adenocarcinomas [5]. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysine tails. Based on their DNA homology, HDACs are divided into class I, II and IV. Class I HDACs (1, 2, 3, and 8) are expressed in many types of cancer; they play an important role in tumorigenesis [6,7,8,9,10,11].
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