1. Epigenetic upregulation of Bak by ZBP-89 inhibits the growth of hepatocellular carcinoma.
- Author
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Ye CG, Chen GG, Ho RLK, Merchant JL, He ML, and Lai PBS
- Subjects
- Acetylation drug effects, Animals, Apoptosis drug effects, Apoptosis genetics, Base Sequence, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Cell Line, Tumor, Cell Proliferation drug effects, CpG Islands genetics, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases metabolism, DNA Methylation drug effects, DNA Methylation genetics, Down-Regulation drug effects, Down-Regulation genetics, Gene Expression Regulation, Neoplastic drug effects, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Humans, Liver Neoplasms genetics, Liver Neoplasms pathology, Mice, Mice, Nude, Molecular Sequence Data, Promoter Regions, Genetic genetics, Protein Binding drug effects, Up-Regulation drug effects, Xenograft Model Antitumor Assays, bcl-2 Homologous Antagonist-Killer Protein metabolism, DNA-Binding Proteins metabolism, Epigenesis, Genetic drug effects, Transcription Factors metabolism, Up-Regulation genetics, bcl-2 Homologous Antagonist-Killer Protein genetics
- 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., (© 2013.)
- Published
- 2013
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