title: AR-42 induces apoptosis in human hepatocellular carcinoma cells via HDAC5 inhibition.
abstract: 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.
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Yida
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Dorfman
authors.affiliation: Department of Gastroenterology, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Zhaogui
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary Surgery, The Eastern Hepatobiliary Surgery Hospital of Second Military Medical University, Shanghai, China.
authors.forename: Fuchen
authors.initials: F
authors.lastname: Liu
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Pathology, The Second Hospital of Anhui Medical University, Anhui Medical University, Hefei, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Dongqin
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.|Collaborative Innovation Center of Genetics and Development, Institutes of Biomedical Sciences and Department of Immunology, Shanghai Medical School, Fudan University, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D010654:Phenylbutyrates / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; C404500:HDAC5 protein, human; D006655:Histone Deacetylases
keywords: AR-42; HDAC5; apoptosis; hepatocellular carcinoma; prognosis