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Signaling and Regulation

Histone Deacetylase Inhibitors Up-Regulate the Expression of Tight Junction Proteins¹

¹ Department of Molecular Biology, University of Geneva, Geneva, Switzerland and² Department of Biology, University of Padova, Padova, Italy

Requests for reprints: Sandra Citi, Department of Molecular Biology, University of Geneva, 30 Quai Ernest Ansermet, 1211 Geneva 4, Switzerland. Phone: 41-22-3796182; Fax: 41-22-3796868. E-mail: Sandra.Citi{at}molbio.unige.ch

Histone deacetylase (HDAC) inhibitors promote cell maturation, differentiation, and apoptosis through changes in gene expression. Differentiated epithelial cells are characterized by apical tight junctions (TJ), which play a role in cell-cell adhesion, polarity, and the permeability barrier function of epithelia. The relationship between cellular differentiation and expression of TJ-associated proteins is not known. Here, we investigated whether HDAC inhibitors affect the expression of TJ proteins in cultured cells by immunoblotting, immunofluorescence, and quantitative real-time, reverse transcription-PCR. We find that the HDAC inhibitor sodium butyrate significantly up-regulates the protein levels of cingulin, ZO-1, and ZO-2 in Rat-1 fibroblasts, cingulin in COS-7 cells, and cingulin and occludin in HeLa cells. Levels of mRNA for cingulin, ZO-1, and ZO-2 are also increased in sodium butyrate–treated Rat-1 fibroblasts. Up-regulation of cingulin is reversible and dose dependent and requires de novo protein synthesis and protein kinase activity, because it is inhibited by cycloheximide and by the protein kinase inhibitor H-7. Up-regulation of TJ proteins by sodium butyrate is linked to the ability of sodium butyrate to inhibit HDAC activity, because suberoylanilide hydroxamic acid, a HDAC inhibitor of a different structural class, also up-regulates cingulin, ZO-1, and ZO-2 expression in Rat-1 fibroblasts. These results indicate that cellular differentiation correlates with kinase-dependent up-regulation of the expression of specific TJ proteins.

Key Words: cingulin • ZO-1 • histone deacetylase inhibitors • differentiation

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