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. J. Cell. Biochem. 116: 2695–2708, 2015. © 2015 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals, Inc.

The Hippo Pathway Effector YAP1 Regulates Intestinal Epithelial Cell Differentiation

“…This finding indicates that the Hippo effector YAP1 not only regulates intestinal stemness [34,36] but also restrains differentiation by repressing expression of pro-differentiation transcription factors such as CDX2. As depicted in Figure 14, this appears to represent another way of repressing intestinal differentiation in the proliferative compartment of the crypt, which adds to other previously identified mechanisms involving polycomb repressive complex 2 and histone deacetylases that mainly inhibit absorptive cell differentiation under a CDX2 independent manner [52,82].…”

Expression profiling of colorectal cancer cells reveals inhibition of DNA replication licensing by extracellular calcium

“…The most upregulated gene in our study was the intestine-specific terminal differentiation marker sucrase-isomaltase, one of the typical differentiation markers of Caco-2 cells [46]. Other upregulated genes were genes involved in xenobiotic detoxification, ion transport, mechanisms linked to differentiation (Table 1).…”

New IL-15 receptor-α splicing variants identified in intestinal epithelial Caco-2 cells

“…32 Interestingly, other alternative splicing variants from cytokine receptors have already been associated to IBD, 33,34 and with human colon cancer IL-8 expression. 35 Moreover, gene expression and alternative splicing are not only dependent on the tissue, but also on epigenetic factors, 21 and changes in the expression of intestinal genes have been found to be related to the inhibition of histone deacetylation 36 and an increased DNA methylation, 37 Several epigenetic mechanisms have been found to be differently regulated in the intestinal mucosa of patients with celiac disease, IBD and colorectal cancer. [38][39][40] Interestingly, the IL-15 gene is hypomethylated in IBD.…”