title: Downregulation of HDAC6 promotes angiogenesis in hepatocellular carcinoma cells and predicts poor prognosis in liver transplantation patients.
abstract: HDAC6, a member of histone deacetylation family, is reported to play critical roles in transcription regulation, cell cycle progression, and cancer development. However, the expression status and significance of HDAC6 in hepatocellular carcinoma (HCC) is still controversial, and little is known about the role of HDAC6 in HCC angiogenesis and the correlation between expression of HDAC6 and prognosis of HCC patients with liver transplantation (LT). Our experiments showed HDAC6 was significantly downregulated in HCC tissues (P = 0.025), and low expression of HDAC6 was found to be closely associated with recurrence (P = 0.006), and could predict poor recurrence-free survival (P = 0.047) for HCC patients with LT. Moreover, knockdown of HDAC6 could promote HUVEC migration, proliferation, and tube formation in vitro, and suppress HCC cell apoptosis, and promote HCC cell proliferation in hypoxia. Remarkably, knockdown of HDAC6 could significantly up-regulate the expression of HIF-1α and VEGFA in vivo and in vitro, which facilitated HIF-1α mediated angiogenesis in HCC. Further study showed that HDAC6 was down-regulated under hypoxia in a time dependent manner. Hence, the present findings suggested a role for suppression of HDAC6 in promoting the angiogenesis in HCC by HIF-1α/VEGFA axis. HDAC6 may serve as a recurrence predictive factor for HCC after LT and pharmacological or genetic activation of HDAC6 could be a novel anti-angiogenesis approach for HCC therapy.
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lv
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang University, Hangzhou, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Weng
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Chengli
authors.initials: C
authors.lastname: Du
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang University, Hangzhou, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang University, Hangzhou, China.
authors.forename: Xianlei
authors.initials: X
authors.lastname: Cai
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang University, Hangzhou, China.
authors.forename: Sunyi
authors.initials: S
authors.lastname: Ye
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang University, Hangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang University, Hangzhou, China.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Ding
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang University, Hangzhou, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang University, Hangzhou, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang University, Hangzhou, China.
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D016031:Liver Transplantation; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D016019:Survival Analysis
chemical_list: C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: HDAC6; angiogenesis; hepatocellular carcinoma; hypoxia; liver transplantation