title: Histone-modifying genes as biomarkers in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is the world's fifth most common cancer and second leading cause of cancer-related death in Taiwan. Over 600,000 HCC patients die each year worldwide despite recent advances in surgical techniques and medical treatments. Epigenetic regulations including DNA methylation and histone modification control gene expressions and play important roles during tumorigenesis. This study evaluates association between histone-modifying genes and prognosis of HCC to ferret out new diagnostic markers. We collected 50 paired HCC and adjacent non-cancerous tissues from Taiwanese patients for survey by RT-qPCR and tissue microarray-based immunohistochemistry (TMA-based IHC) staining. RT-qPCR data showed four of twenty-four genes over eightfold up-regulated in tumor tissues: e.g., histone phosphorylation gene-ARK2, methylation genes-G9a, SUV39H2, and EZH2 (n=50, all p<0.0001). Results of TMA-based IHC staining showed proteins of ARK2, EZH2, G9a, and SUV39H2 also overexpressed in tumor tissues. Staining intensity of SUV39H2 correlated with HCV infection (p=0.025). We further restricted the analysis only in tumor tissues, we found EZH2 staining intensity associated with tumor stage (p=0.016) and survival (p=0.007); SUV39H2 intensity associated with tumor stage (p=0.044). Our findings indicate overexpression of histone-modifying genes EZH2 and SUV39H2 associated with prognosis of HCC cases. EZH2 expression can serve as a novel prognostic biomarker during HCC progression among Taiwanese.
authors: Epigenome Research Center, China Medical University Hospital Taichung 40447, Taiwan ; Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University Taichung 40402, Taiwan.
authors: Shih-Ya
authors: SY
authors: Hung
authors: Epigenome Research Center, China Medical University Hospital Taichung 40447, Taiwan.
authors: Hui-Hua
authors: HH
authors: Lin
authors: Departmant of Pathology, Changhua Christian Hospital Changhua 50006, Taiwan.
authors: Kun-Tu
authors: KT
authors: Yeh
authors: Epigenome Research Center, China Medical University Hospital Taichung 40447, Taiwan ; Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University Taichung 40402, Taiwan ; Department of Laboratory Medicine, China Medical University Hospital Taichung 40447, Taiwan ; School of Medicine, China Medical University Taichung 40447, Taiwan.
authors: Jan-Gowth
authors: JG
authors: Chang
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000821:virology; D000071221:Enhancer of Zeste Homolog 2 Protein; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016174:Hepacivirus / Q000302:isolation & purification; D011495:Histone-Lysine N-Methyltransferase / Q000032:analysis* / Q000235:genetics; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000821:virology; D008745:Methylation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000032:analysis* / Q000235:genetics; D011237:Predictive Value of Tests; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D013624:Taiwan; D013997:Time Factors; D046888:Tissue Array Analysis; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; D012333:RNA, Messenger; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; C515701:SUV39H2 protein, human
keywords: Hepatocellular carcinoma; histone acetylation; histone methylation; histone modification; histone phosphorylation