title: Hepatitis C virus core upregulates the methylation status of the RASSF1A promoter through regulation of SMYD3 in hilar cholangiocarcinoma cells.
abstract: Increasing evidence has been accumulated indicating the important role of epigenetic regulation in tumor genesis. Previously, we observed that the transfection of hepatitis C virus core (HCVc) protein led to malignant transformation in normal biliary cells, and that tumor suppressor gene RASSF1A was downregulated in many hilar cholangiocarcinoma patients by hypermethylation in the promoter region. In the present study, we found SET and MYND domain-containing protein 3 (SMYD3), a novel histone methyltransferase, was overexpressed in cholangiocarcinoma patients especially in those with HCV infection. Transfection of HCVc into hilar cholangiocarcinoma cell lines QBC939 and FRH0201 could upregulate the expression of SMYD3 and promote cell growth, which was consistent with the results of our clinical research. This phenomenon indicated that SMYD3 was related to the epigenetic regulation of cholangiocarcinoma genesis with HCV infection. Overexpression of SMYD3 could inhibit RASSF1A expression, whereas inhibition of SMYD3 by siRNA improved its expression. Methylation-specific polymerase chain reaction (MS-PCR) results showed the methylation status of RASSF1A promoter was regulated by SMYD3. In conclusion, HCVc could upregulate the methylation status of the RASSF1A promoter through regulation of SMYD3, and histone methylation may affect the DNA methylation of downstream gene by an unknown mechanism.
authors: Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China.
authors: Ning
authors: N
authors: Guo
authors: Rufu
authors: R
authors: Chen
authors: Zhihua
authors: Z
authors: Li
authors: Yonggang
authors: Y
authors: Liu
authors: Di
authors: D
authors: Cheng
authors: Quanbo
authors: Q
authors: Zhou
authors: Jiajia
authors: J
authors: Zhou
authors: Qing
authors: Q
authors: Lin
mesh_terms: D001483:Base Sequence; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D015153:Blotting, Western; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation / Q000276:immunology*; D017931:DNA Primers; D018936:Hepatitis C Antigens / Q000276:immunology*; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D016133:Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; D018936:Hepatitis C Antigens; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human