title: Epigenetic upregulation of Bak by ZBP-89 inhibits the growth of hepatocellular carcinoma.
abstract: Zinc-binding protein-89 regulates Bak to facilitate apoptosis in cancer cells. This study examined if zinc-binding protein-89 regulates Bak through an epigenetic mechanism in hepatocellular carcinoma. We first demonstrated that the expression of Bak was reduced but the levels of deoxyribonucleic acid methyltransferase 1 and histone deacetylase 3 were increased in hepatocellular carcinoma cancer tissues compared to the corresponding non-cancer tissues. Moreover, there was a negative correlation between Bak expression and deoxyribonucleic acid methyltransferase 1 levels in hepatocellular carcinoma. Administration of zinc-binding protein-89 downregulated histone deacetylase 3 expression and suppressed the activities of histone deacetylase and deoxyribonucleic acid methyltransferase, which led to maintenance of histone acetylation status, inhibited the binding of methyl-CpG-binding protein 2 to genomic deoxyribonucleic acid and demethylated CpG islands in the Bak promoter in hepatocellular carcinoma cells. Using the xenograft mouse tumor model, we demonstrated that zinc-binding protein-89 or inhibitors of either epigenetic enzymes could stimulate Bak expression, induce apoptosis, and arrest tumor growth and that the maximal effort was achieved when zinc-binding protein-89 and the enzyme inhibitors were used in combination. Conclusively, zinc-binding protein-89 upregulates the expression of Bak by targeting multiple components of the epigenetic pathway in hepatocellular carcinoma.
authors: Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; China-America Cancer Research Institute, Guangdong Medical College, Dongguan 523808, PR China.
authors: Cai Guo
authors: CG
authors: Ye
authors: Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. Electronic address: gchen@cuhk.edu.hk.
authors: George G
authors: GG
authors: Chen
authors: Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors: Rocky L K
authors: RLK
authors: Ho
authors: Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Juanita L
authors: JL
authors: Merchant
authors: Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors: Ming-Liang
authors: ML
authors: He
authors: Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors: Paul B S
authors: PBS
authors: Lai
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018899:CpG Islands / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics* / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D014157:Transcription Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D000099186:Histone Deacetylase 3; C110951:ZNF148 protein, human
keywords: 5-Aza-dC; 5-aza-2′-deoxycytidine; Bak; ChIP; Co-IP; DNA methyltransferase; DNMT; HCC; HDAC; Hepatocellular carcinoma; MIHA; MeCP2; VPA; ZBP-89; Zebu; chromatin immunoprecipitation; co-immunoprecipitation; hepatocellular carcinoma; histone deacetylase; immortalized non-tumorigenic hepatocyte cell line; methyl-CpG-binding protein 2; sodium valproic acid; zebularine
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