A Novel Chalcone Polyphenol Inhibits the Deacetylase Activity of SIRT1 and Cell Growth in HEK293T Cells

Abstract

Abstract. SIRT1 is one of seven mammalian orthologs of yeast silent information regulator 2 (Sir2), and it functions as a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase. Recently, resveratrol and its analogues, which are polyphenols, have been reported to activate the deacetylase activity of SIRT1 in an in vitro assay and to expand the life-span of several species through Sir2 and the orthologs. To find activators or inhibitors to SIRT1, we examined thirty-six polyphenols, including stilbenes, chalcones, flavanones, and flavonols, with the SIRT1 deacetylase activity assay using the acetylated peptide of p53 as a substrate. The results showed that 3,2',3',4'-tetrahydroxychalcone, a newly synthesized compound, inhibited the SIRT1-mediated deacetylation of a p53 acetylated peptide and recombinant protein in vitro. In addition, this agent induced the hyperacetylation of endogenous p53, increased the endogenous p21 CIP1/ WAF1 in intact cells, and suppressed the cell growth. These results indicated that 3,2',3',4'-tetrahydroxychalcone had a stronger inhibitory effect on the SIRT1-pathway than sirtinol, a known SIRT1-inhibitor. Our results mean that 3,2',3',4'-tetrahydroxychalcone is a novel inhibitor of SIRT1 and produces physiological effects on organisms probably through inhibiting the deacetylation by SIRT1.

Effect of long-term piceatannol treatment on eNOS levels in cultured endothelial cells

“…In endothelial cells, up-regulation of eNOS mRNA by treatment with resveratrol is prevented by knockdown of SIRT1 [37]. Piceatannol and resveratrol activate the deacetylase activity of SIRT1, and the effect of piceatannol is reported to be higher than that of resveratrol [38]. Strong up-regulation of eNOS mRNA by piceatannol is considered to be partly due to the activation of SIRT1.…”

p53-based Cancer Therapy

“…3,2 0 ,3 0 ,4 0 -tetrahydroxychalcone is a polyphenol identified as an inhibitor of purified SirT1's ability to deacetylate recombinant p53 and a p53 derived peptide (Kahyo et al 2008). In cells, this agent suppressed the cell growth, induced the hyperacetylation of endogenous p53 and increased endogenous p21 CIP1/WAF1 expression.…”

Identification of Bichalcones as Sirtuin Inhibitors by Virtual Screening and <em>in Vitro </em>Testing

“…It could be suggested that, unlike the rhuschalcones, both C-C and C-O linked non-symmetrical bichalcones be also be synthesized tested against the sirtuins, with the view of investigating potential selectivities against the isoforms. Besides, chalcones have previously shown deacetylase inhibitory properties against sirt1 and cell growth in HEK293T cells [53]. In order to rationalize the interaction of the identified hits in our study, all docking poses for sirt1 (PDB ID: 4ZZJ) and sirt2 (PDB ID: 4R8M and PDB ID: 5D7P) were analyzed using the MOE program [54].…”