Aryl hydrocarbon receptor regulates histone deacetylase 8 expression to repress tumor suppressive activity in hepatocellular carcinoma.
Histone deacetylase 8 (HDAC8), a unique member of class I histone deacetylases, shows remarkable correlation with advanced disease stage and multiple malignant tumors However, little is known about the contribution of HDAC8 to the tumorigenesis of hepatocellular carcinoma (HCC). The present study investigated the expression of HDAC8 regulated by the aryl hydrocarbon receptor (AHR) in HCC cell lines and tissues, and the roles of HDAC8 overexpression in cell proliferation, including potentially underlying mechanisms. We assessed the correlation between the clinic-pathological parameters and the expression of AHR and HDAC8. Further, we analyzed the AHR siRNA transfection and HDAC8 inhibitors to explore the functions of HDAC8 in HCC progression in vitro and in vivo. In a panel of 289 HCC patients, HDAC8 was shown to be highly correlated with AHR expression at both mRNA and protein levels. HCC patients with high AHR expression showed a shorter survival time than that with low AHR expression. We then found that the expression of both AHR and HDAC8 was significantly upregulated in both HCC cell lines and tumor tissues compared to human normal hepatocytes and matched non-tumor tissues. Furthermore, HDAC8 inhibition remarkably inhibited hepatoma cell proliferation and transformation activity via upregulation of RB1 in vitro and in vivo. Our data revealed an important role of the AHR-HDAC8 axis in promoting HCC tumorigenesis, thus identifying HDAC8 as a potential therapeutic target for HCC treatment.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Li-Ting
LT
Wang
Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.|Division of Hematology-Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
Shyh-Shin
SS
Chiou
Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Chee-Yin
CY
Chai
Department of Genome Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Edward
E
Hsi
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.|Division of Hepatobiliary Surgery, Department of Surgery, Kaohsiung Medical University, Kaohsiung 807, Taiwan.|Department of Surgery, faculty of Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
Shen-Nien
SN
Wang
Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan 115, Taiwan.|Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Shau-Ku
SK
Huang
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.|Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.|Center of Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Shih-Hsien
SH
Hsu
D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D056286:Retinoblastoma Binding Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases; C111235:AHR protein, human; C000606393:RB1 protein, human; C409470:HDAC8 protein, human
AHR; HDAC8; hepatocellular carcinoma (HCC)