AR-42 induces apoptosis in human hepatocellular carcinoma cells via HDAC5 inhibition
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Mingming Zhang1, Yida Pan1, Robert G. Dorfman3, Zhaogui Chen4, Fuchen Liu5, Qian Zhou6, Shan Huang7, Jun Zhang1, Dongqin Yang1, Jie Liu1,2
1Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China
2Collaborative Innovation Center of Genetics and Development, Institutes of Biomedical Sciences and Department of Immunology, Shanghai Medical School, Fudan University, Shanghai, China
3Northwestern University Feinberg School of Medicine, Chicago, IL, USA
4Department of Gastroenterology, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
5Department of Hepatobiliary Surgery, The Eastern Hepatobiliary Surgery Hospital of Second Military Medical University, Shanghai, China
6School of Life Sciences, Fudan University, Shanghai, China
7Department of Pathology, The Second Hospital of Anhui Medical University, Anhui Medical University, Hefei, China
Dongqin Yang, e-mail: [email protected]
Jie Liu, e-mail: [email protected]
Keywords: AR-42, apoptosis, hepatocellular carcinoma, HDAC5, prognosis
Received: May 11, 2015 Accepted: February 23, 2016 Published: March 14, 2016
Histone deacetylases (HDACs) play critical roles in apoptosis and contribute to the proliferation of cancer cells. AR-42 is a novel Class I and II HDAC inhibitor that shows cytotoxicity against various human cancer cell lines. The present study aims to identify the target of AR-42 in hepatocellular carcinoma (HCC) as well as evaluate its therapeutic efficacy. We found that HDAC5 was upregulated in HCC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. CCK8 and colony-formation assays showed that HDAC5 overexpression promotes proliferation in HCC cell lines. Treatment with AR-42 decreased HCC cell growth and increased caspase-dependent apoptosis, and this was rescued by HDAC5 overexpression. We demonstrated that AR-42 can inhibit the deacetylation activity of HDAC5 and its downstream targets in vitro and in vivo. Taken together, these results demonstrate for the first time that AR-42 targets HDAC5 and induces apoptosis in human hepatocellular carcinoma cells. AR-42 therefore shows potential as a new drug candidate for HCC therapy.
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