HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Mol Cancer Ther. 2015 Nov;14(11):2623-33. doi: 10.1158/1535-7163.MCT-15-0025. Epub 2015 Sep 10.

Abstract

Hepatocellular carcinoma (HCC) can arise from chronic inflammation due to viral infection, organ damage, drug toxicity, or alcohol abuse. Moreover, gene desensitization via aberrant CpG island methylation is a frequent epigenetic defect in HCC. However, the details of how inflammation is linked with epigenetic-mediated desensitization of tumor suppressor genes remains less investigated. In this study, we found that loss of CEBPD enhances the growth of liver cancer cells and is associated with the occurrence of liver cancers, as determined by the assessment of clinical specimens and in vivo animal models. Moreover, E2F1-regulated epigenetic axis attenuated CEBPD expression in liver cancer cells. CEBPD is responsive to the hydroxymethyldibenzoylmethane (HMDB)-induced p38/CREB pathway and plays an important role in the HMDB-induced apoptosis of cancer cells. Regarding depression of epigenetic effects to enhance HMDB-induced CEBPD expression, the combination of HMDB and 5-Aza-2'-deoxycytidine (5-AzadC) could enhance the death of liver cancer cells and reduce the tumor formation of Huh7 xenograft mice. In conclusion, these results suggest that CEBPD could be a useful diagnostic marker and therapeutic target in HCC. The results also reveal the therapeutic potential for low-dose 5-AzadC to enhance the HMDB-induced death of HCC cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Azacitidine / administration & dosage
  • Azacitidine / analogs & derivatives*
  • Azacitidine / pharmacology
  • Blotting, Western
  • CCAAT-Enhancer-Binding Protein-delta / antagonists & inhibitors*
  • CCAAT-Enhancer-Binding Protein-delta / genetics
  • CCAAT-Enhancer-Binding Protein-delta / metabolism
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Decitabine
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hep G2 Cells
  • Humans
  • Immunohistochemistry
  • Ketones / administration & dosage
  • Ketones / pharmacology*
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Mice, Inbred NOD
  • Mice, SCID
  • Oligonucleotide Array Sequence Analysis
  • Propane / administration & dosage
  • Propane / analogs & derivatives*
  • Propane / pharmacology
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Xenograft Model Antitumor Assays

Substances

  • 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione
  • E2F1 Transcription Factor
  • Ketones
  • CCAAT-Enhancer-Binding Protein-delta
  • Decitabine
  • Azacitidine
  • Propane