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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, RESULTS. Meshes: Acetylation, Blotting, Western, Butyrates, Caco-2 Cells, Cell Line, Tumor, Cell Proliferation, Colonic Neoplasms, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, HT29 Cells, Hepatocyte Nuclear Factor 4, Histone Deacetylase Inhibitors, Histone Deacetylases, Histones, Humans, Hydroxamic Acids, Mucin-4, Promoter Regions, Genetic, Protein Binding, RNA Interference, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Sp1 Transcription Factor, Transcription, Genetic.
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Does epigenetic control of HNF-4α in colon carcinoma cells affect MUC4 expression and malignancy? Context: We previously found that enhanced expression of hepatocyte nuclear factor 4α (HNF-4α) is associated with hyper-proliferation of colon carcinoma cells. Here, the effect of histone deacetylase (HDAC) inhibitors on proliferation and the expression of HNF-4α and its downstream target genes were assessed in HM7, LS174T, HT29 and Caco-2 colon carcinoma cell lines. HNF-4α expression was found to vary in the different colon carcinoma cell lines tested, being highest in HM7. Additionally, a direct correlation with proliferation was observed. In HM7 cells, the weak HDAC inhibitor butyrate significantly inhibited the transcription of HNF-4α, its downstream target gene MUC4, and genes associated with proliferation, including the proliferating cell nuclear antigen gene PCNA. siRNA-mediated silencing of HNF-4α exerted an effect similar to butyrate on HM7 cell proliferation. The stronger HDAC inhibitor trichostatin A (TSA) exerted an effect similar to that of siRNA-mediated HNF-4α silencing and, concomitantly, inhibited the expression of the transcription factor gene SP1. Also, siRNA-mediated silencing of HDAC3 and HDAC4 reduced HNF-4α expression. Chromatin immunoprecipitation (ChIP) assays revealed that TSA induces hyperacetylation of histones H3 and H4 and, concomitantly, inhibits SP1 binding to the HNF-4α promoter. Subsequent electromobility shift assays supported these latter findings.
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HNF-4α transcriptional expression and activity are tightly controlled by epigenetic mechanisms. HDAC inhibitor targeting of HNF-4α may serve as an effective treatment for advanced colon carcinomas, since downstream cancer-associated target genes such as MUC4 are significantly down-regulated by this treatment. Final Decision: yes