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Gene expression associated with the decrease in malignant phenotype of human liver cancer cells following stimulation with a histone deacetylase inhibitor.

Kanji Wakabayashi·Hidetsugu Saito·Fumihiko Kaneko·Nobuhiro Nakamoto·Shinichiro Tada·Toshifumi Hibi
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Abstract

Sodium butyrate is a short-chain fatty acid produced by fermentation in the gastrointestinal tract. It induces differentiation of several kinds of cancer by inhibiting histone deacetylase activity. We have reported that butyrate stimulates hepatocellular carcinoma cells into their normal phenotype. Since sodium butyrate affects both differentiation and apoptosis, we investigated expression of bcl-2-related genes in a human hepatocellular carcinoma cell line HCC-T. The expression of anti-apoptotic Bcl-2 and Mcl-1/EAT was up-regulated 4 h after the treatment, while pro-apoptotic Bax expression did not change. Gene expressions in the early stage of butyrate-stimulation were investigated by the differential display assay and the cDNA expression array. Laminin and keratin 18 were increased 6 h after the stimulation with sodium butyrate. The results of cDNA expression array revealed up-regulation of cell cycle inhibitory genes such as cyclin-dependent kinase 4 inhibitor, and interferon-related genes such as STAT2 and 3, while down-regulation of cyclin-dependent kinase 2 and cyclin E. Up-regulated production of p21WAF-1 and Mcl-1/EAT was also confirmed by Western blotting. The cytoskeletal change indicated by up-regulation of laminin and keratin 18 may be an important factor in the decrease in malignant phenotype of cancer cells. Up-regulation of interferon-related genes indicated that butyrate-treatment might induce a similar phenotypic change to that induced by type 1 interferons. This study suggests several target genes for the future gene therapy of cancer or genes preventing cancer development from pre-malignant tissues.

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Antineoplastic AgentsApoptosisButyratesCDC2-CDC28 KinasesCarcinoma, HepatocellularCell Cycle ProteinsCell Line, TumorCyclin ECyclin-Dependent Kinase 2Cyclin-Dependent Kinase Inhibitor p21Down-RegulationEnzyme InhibitorsGene ExpressionGene Expression ProfilingHistone Deacetylase InhibitorsHistone DeacetylasesHumansIsobutyratesKeratin-18KeratinsLamininLiver NeoplasmsMyeloid Cell Leukemia Sequence 1 ProteinNeoplasm ProteinsOligonucleotide Array Sequence AnalysisProto-Oncogene Proteins c-bcl-2Up-RegulationJournal Article

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Kanji Wakabayashi, Hidetsugu Saito, Fumihiko Kaneko, Nobuhiro Nakamoto, Shinichiro Tada, Toshifumi Hibi. 2005. Gene expression associated with the decrease in malignant phenotype of human liver cancer cells following stimulation with a histone deacetylase inhibitor.. https://pubmed.ncbi.nlm.nih.gov/15586245/

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