Epigenetic control of HNF-4α in colon carcinoma cells affects MUC4 expression and malignancy

Anna Algamas-Dimantov, Einav Yehuda-Shnaidman, Irena Peri, Betty Schwartz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Background: 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. Results: 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. Conclusions: 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.

Original languageAmerican English
Pages (from-to)155-167
Number of pages13
JournalCellular oncology (Dordrecht)
Volume36
Issue number2
DOIs
StatePublished - Apr 2013

Bibliographical note

Funding Information:
This work was supported by the Israel Science Foundation; Grant number: 134/06.

Keywords

  • Colon carcinoma
  • HDAC inhibitors
  • HNF-4α
  • MUC4

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