title: Histone deacetylase inhibition impairs normal intestinal cell proliferation and promotes specific gene expression.
abstract: Mechanisms that maintain proliferation and delay cell differentiation in the intestinal crypt are not yet fully understood. We have previously shown the implication of histone methylation in the regulation of enterocytic differentiation. In this study, we investigated the role of histone deacetylation as an important epigenetic mechanism that controls proliferation and differentiation of intestinal cells using the histone deacetylase inhibitor suberanilohydroxamic acid (SAHA) on the proliferation and differentiation of human and mouse intestinal cells. Treatment of newly confluent Caco-2/15 cells with SAHA resulted in growth arrest, increased histone acetylation and up-regulation of the expression of intestine-specific genes such as those encoding sucrase-isomaltase, villin and the ion exchanger SLC26A3. Although SAHA has been recently used in clinical trials for cancer treatment, its effect on normal intestinal cells has not been documented. Analyses of small and large intestines of mice treated with SAHA revealed a repression of crypt cell proliferation and a higher expression of sucrase-isomaltase in both segments compared to control mice. Expression of SLC26A3 was also significantly up-regulated in the colons of mice after SAHA administration. Finally, SAHA was also found to strongly inhibit normal human intestinal crypt cell proliferation in vitro. These results demonstrate the important implication of epigenetic mechanisms such as histone acetylation/deacetylation in the regulation of normal intestinal cell fate and proliferation.
authors.affiliation: Laboratory of Intestinal Physiopathology, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.|Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.
authors.forename: Alireza
authors.initials: A
authors.lastname: Roostaee
authors.affiliation: Laboratory of Intestinal Physiopathology, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.|Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.
authors.forename: Amel
authors.initials: A
authors.lastname: Guezguez
authors.affiliation: Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.
authors.forename: Marco
authors.initials: M
authors.lastname: Beauséjour
authors.affiliation: Laboratory of Intestinal Physiopathology, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.
authors.forename: Aline
authors.initials: A
authors.lastname: Simoneau
authors.affiliation: Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.
authors.forename: Pierre H
authors.initials: PH
authors.lastname: Vachon
authors.affiliation: Department of Nutrition, Université de Montréal, and Research Center, Sainte-Justine UHC, Montréal, Québec, Canada, H3T 1C5.
authors.forename: Emile
authors.initials: E
authors.lastname: Levy
authors.affiliation: Laboratory of Intestinal Physiopathology, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.|Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Beaulieu
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D027963:Chloride-Bicarbonate Antiporters / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D013394:Sucrase-Isomaltase Complex / Q000235:genetics / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D027963:Chloride-Bicarbonate Antiporters; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D013394:Sucrase-Isomaltase Complex
keywords: DIFFERENTIATION; HDAC INHIBITION; INTESTINAL CELLS; PROLIFERATION; SAHA