Epigenetic regulation of the human mucin gene MUC4 in epithelial cancer cell lines involves both DNA methylation and histone modifications mediated by DNA methyltransferases and histone deacetylases - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue FASEB Journal Année : 2008

Epigenetic regulation of the human mucin gene MUC4 in epithelial cancer cell lines involves both DNA methylation and histone modifications mediated by DNA methyltransferases and histone deacetylases

Résumé

The human gene MUC4 encodes a trans-membrane mucin, ligand of ErbB2, that is associated with pancreatic tumor progression. In the normal pan-creas, MUC4 is not expressed, whereas activation of its expression is observed in the early steps of pancreatic carcinogenesis. The molecular mechanisms responsible for MUC4 gene activation are however still unknown. The MUC4 5-flanking region being GC-rich and including two CpG islands, we hypothesized that epigenetic regulation may be involved and undertook to decipher the molecular phenomenons implied. By treating cancer cell lines with 5-aza-2-deoxycytidine (5-aza) and trichostatin A (TSA), we were able to restore MUC4 expression in a cell-specific manner. We showed by bisulfite-treated genomic DNA sequencing and chroma-tin immunoprecipitation that methylation of five CpG sites and establishment of a repressive histone code at the 5-untranslated region were associated with MUC4 silencing and impaired its activation by Sp1. Direct involvement of DNMT3A, DNMT3B, HDAC1, and HDAC3 was demonstrated by RNA interference and chromatin immunoprecipitation. Moreover, inhibition of histone deacetylation by TSA was associated with strong MUC4 repression in high-expressing cells. In conclusion, this work shows for the first time the importance of epigenetics in regulating MUC4 expression and may represent a new strategy to inhibit its expression in epithelial tumors-Vincent, A., Ducour-ouble, M.-P., Van Seuningen, I. Epigenetic regulation of the human mucin gene MUC4 in epithelial cancer cell lines involves both DNA methylation and histone modifications mediated by DNA methyltransferases and his-tone deacetylases.
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Dates et versions

hal-02905794 , version 1 (02-10-2020)

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Audrey Vincent, Marie-Paule Ducourouble, Isabelle Van Seuningen. Epigenetic regulation of the human mucin gene MUC4 in epithelial cancer cell lines involves both DNA methylation and histone modifications mediated by DNA methyltransferases and histone deacetylases. FASEB Journal, 2008, 22 (8), pp.3035-3045. ⟨10.1096/fj.07-103390⟩. ⟨hal-02905794⟩

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