Epigenetic upregulation of Bak by ZBP-89 inhibits the growth of hepatocellular carcinoma

Cai Guo Ye, George G. Chen, Rocky L.K. Ho, Juanita L. Merchant, Ming Liang He, Paul B.S. Lai

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2970-2979
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1833
Issue number12
DOIs
StatePublished - Dec 2013
Externally publishedYes

Keywords

  • Bak
  • DNMT
  • HDAC
  • Hepatocellular carcinoma
  • ZBP-89

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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