Abstract
Histone deacetylase 3 (HDAC3) has an oncogenic role in apoptosis and contributes to the proliferation of cancer cells. MI192 is a novel HDAC3-specific inhibitor that displays antitumor activity in many cancer cell lines. However, the role of HDAC3 and the antitumor activity of its inhibitor MI192 are not known in cholangiocarcinoma (CCA). The present study aims to identify the target of MI192 in CCA as well as evaluate its therapeutic efficacy. CCK8 and colony formation assays showed that HDAC3 overexpression promotes proliferation in CCA cell lines. HDAC3 knockdown or treatment with MI192 decreased CCA cell growth and increased caspase-dependent apoptosis, while apoptosis was partially rescued by HDAC3 overexpression. We demonstrated that MI192 can inhibit the deacetylation activity of HDAC3 and its downstream targets in vitro, and MI192 inhibited xenograft tumor growth in vivo. Immunochemistry showed that HDAC3 was upregulated in CCA tissues compared with adjacent normal tissues, and this was correlated with reduced patient survival. Taken together, these results demonstrate for the first time that MI192 targets HDAC3 and induces apoptosis in human CCA cells. MI192 therefore shows the potential as a new drug candidate for CCA therapy.
Highlights
Cholangiocarcinoma (CCA) is a highly malignant adenocarcinoma with increasing mortality in many countries.[1,2,3] Most patients are diagnosed at late stages and are not eligible for surgical resection or liver transplantation
Studies showed that high levels of HDAC3 expression and activity had a critical role in cell epigenetic alterations associated with malignancies.[13,14]
Numerous reports indicate that histone deacetylases (HDACs) are overexpressed in many cancers and inhibit specific tumor suppressor genes, thereby resulting in aberrant epigenetics in cancer cells.[11,12]
Summary
Cholangiocarcinoma (CCA) is a highly malignant adenocarcinoma with increasing mortality in many countries.[1,2,3] Most patients are diagnosed at late stages and are not eligible for surgical resection or liver transplantation. Histone acetylation is typically associated with increased transcription, and histone deacetylases (HDACs) are regulatory enzymes that catalyze the removal of acetyl groups from histones According to their homology, the 11 HDACs can be divided into Classes I, II and IV.[5] Class I HDACs (1, 2, 3 and 8) have an important role in tumorigenesis and may be candidate targets for many cancer treatments.[6,7,8,9,10] Numerous reports indicate that Class I HDACs are overexpressed in many cancers and inhibit specific tumor suppressor genes, resulting in an aberrant epigenetic status compared with adjacent normal cells.[11,12] Recently, studies showed that high levels of HDAC3 expression and activity had a critical role in cell epigenetic alterations associated with malignancies.[13,14] the role of HDAC3 in CCA has not been elucidated
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