Histone deacetylase inhibitor screening identifies HC toxin as the most effective in intrahepatic cholangiocarcinoma cells

Zhou,Wenjie; Chen,Xiaoxun; He,Ke; Xiao,Jinfeng; Duan,Xiaopeng; Huang,Rui; Xia,Zhenglin; He,Jingliang; Zhang,Jinqian; Xiang,Guoan

doi:10.3892/or.2016.4636

Histone deacetylase inhibitor screening identifies HC toxin as the most effective in intrahepatic cholangiocarcinoma cells

Authors:
- Wenjie Zhou
- Xiaoxun Chen
- Ke He
- Jinfeng Xiao
- Xiaopeng Duan
- Rui Huang
- Zhenglin Xia
- Jingliang He
- Jinqian Zhang
- Guoan Xiang
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Affiliations: Department of General Surgery, The Second People's Hospital of Guangdong Province, The Third Clinical Medical College of Southern Medical University, Guangzhou, Guangdong 510317, P.R. China, Department of Gastrointestinal Surgery, The Guigang City People's Hospital, Guigang, Guangxi 537100, P.R. China, Graduate School, Guangdong Medical College, Zhanjiang, Guangdong 524023, P.R. China, Department of Laboratory Medicine, The Second People's Hospital of Guangdong Province, Guangzhou, Guangdong 510317, P.R. China
Published online on: February 25, 2016 https://doi.org/10.3892/or.2016.4636
Pages: 2535-2542
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Histone deacetylases (HDACs) are highly expressed in intrahepatic cholangiocarcinoma (ICC) and are associated with poor prognosis of these patients. The aim of the present study was to explore the inhibitory effects of HDAC inhibitors on ICC cells and identify effective and sensitive drugs for ICC. Effects of 34 HDAC inhibitors were screened through two rounds of cell viability assays, and HC toxin, a cyclic tetrapeptide first isolated from the secondary metabolite of Helminthosporium carbonum, exhibited an antitumor activity superior to that of the other HDAC inhibitors and gemcitabine. The mechanisms involved in the inhibitory effects of HC toxin on CCLP-1 cells were investigated by cell counting, colony formation assay, cell morphological observation, real-time PCR, western blotting and flow cytometry. It was demonstrated that HC toxin inhibited the cell proliferation and clone formation ability of the CCLP-1 cells. HC toxin increased the acetyl-histone H4 level and this was associated with the inhibitory effect of HC toxin on the CCLP-1 cells. We also found that HC toxin reduced the level of HDAC1 protein in a post-transcriptional manner. Morphological observation showed multiple morphological changes and indicated the possibility of cell differentiation owing to HC toxin. With increasing concentration of HC toxin, the cell cycle was gradually arrested at the G0/G1 stage and the percentage of apoptotic cells increased which was not mainly through the caspase-3-dependent ways. These results indicated that HC toxin was the most effective among the various HDAC inhibitors with multiple functions in the suppression of ICC in vitro. Thus, HC may be a potential chemotherapeutic for ICC.

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