Inhibition of Histone Deacetylase Activity by Butyrate

Abstract

This article reviews the effects of the short-chain fatty acid butyrate on histone deacetylase (HDAC) activity. Sodium butyrate has multiple effects on cultured mammalian cells that include inhibition of proliferation, induction of differentiation and induction or repression of gene expression. The observation that butyrate treatment of cells results in histone hyperacetylation initiated a flurry of activity that led to the discovery that butyrate inhibits HDAC activity. Butyrate has been an essential agent for determining the role of histone acetylation in chromatin structure and function. Interestingly, inhibition of HDAC activity affects the expression of only 2% of mammalian genes. Promoters of butyrate-responsive genes have butyrate response elements, and the action of butyrate is often mediated through Sp1/Sp3 binding sites (e.g., p21(Waf1/Cip1)). We demonstrated that Sp1 and Sp3 recruit HDAC1 and HDAC2, with the latter being phosphorylated by protein kinase CK2. A model is proposed in which inhibition of Sp1/Sp3-associated HDAC activity leads to histone hyperacetylation and transcriptional activation of the p21(Waf1/Cip1) gene; p21(Waf1/Cip1) inhibits cyclin-dependent kinase 2 activity and thereby arrests cell cycling. Pending the cell background, the nonproliferating cells may enter differentiation or apoptotic pathways. The potential of butyrate and HDAC inhibitors in the prevention and treatment of cancer is presented.

HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism

“…As HDAC3 silencing did not increase p21 WAF1/Cip1 expression in IGROV-1 cells (Figure 1b), it is also possible that the mechanism by which HDAC4 represses the p21 WAF1/Cip1 promoter varies between cell types. We found that Sp1 physically associates with HDAC4 and HDAC1, but does not interact with HDAC3 as reported (Doetzlhofer et al, 1999;Sun et al, 2002;Davie, 2003;He et al, 2005;Kang et al, 2005). We therefore speculate that HDAC4 participates, with a HDAC1-dependent co-repressor complex, in p21 WAF1/Cip1 repression.…”

Genetic networks responsive to sodium butyrate in colonic epithelial cells

“…Effects of SB on the expression level of acetylated histone H2B As butyrate is known to induce histone acetylation [4,8], the degree of this acetylation was examined. Western blot analysis using an anti-acetylated histone H2B antibody showed that SB at a concentration of 2 mM significantly induced the accumulation of acetylated histone H2B under 6, 12 and 24 h of SB treatment, with levels that were approximately 3.5 times higher than those of control cells (0 h) ( Fig.…”

Histone deacetylase modulators provided by Mother Nature

“…3). It has been shown that butyrate inhibits HDAC classes I, IIa and IV (Davie 2003). This compound leads to growth arrest, differentiation of leukemic cells and induces apoptosis following the deterioration of the anti-apoptotic protein Bcl-2 (Rosato et al 2003;Schnekenburger et al 2006).…”