A Novel Chalcone Polyphenol Inhibits the Deacetylase Activity of SIRT1 and Cell Growth in HEK293T Cells
A Novel Chalcone Polyphenol Inhibits the Deacetylase Activity of SIRT1 and Cell Growth in HEK293T Cells
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DOI：
10.1254/jphs.08203fp
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发表时间：
2008-11-01
影响因子：
3.5
通讯作者：
Setou, Mitsutoshi
中科院分区：
文献类型：
--
作者：
Kahyo, Tomoaki;Ichikawa, Shuji;Setou, Mitsutoshi
SIRT 1是酵母沉默信息调节因子2（Sir 2）的七种哺乳动物直向同源物之一，并且其作为烟酰胺腺嘌呤二核苷酸（NAD）依赖性脱乙酰酶发挥功能。最近，白藜芦醇及其类似物，这是多酚，已被报道激活SIRT 1的脱乙酰酶活性在体外试验中，并通过Sir 2和直系同源物延长几个物种的寿命。为了找到SIRT 1的激活剂或抑制剂，我们检测了36种多酚，包括芪类、查耳酮、黄烷酮和黄酮醇，使用p53的乙酰化肽作为底物进行SIRT 1脱乙酰酶活性测定。结果表明，新合成的化合物3，2 '，3'，4 '-四羟基查耳酮在体外可抑制SIRT 1介导的p53乙酰化肽和重组蛋白的脱乙酰化。此外，该试剂诱导内源性p53的过度乙酰化，增加完整细胞中的内源性p21（CIPI/WAFI），并抑制细胞生长。这些结果表明，3，2 '，3'，4 '-四羟基查耳酮对SIRT 1-途径的抑制作用强于已知的SIRT 1-抑制剂sirtinol。我们的研究结果表明，3，2 '，3'，4 '-四羟基查耳酮是一种新的SIRT 1抑制剂，可能通过抑制SIRT 1的脱乙酰化而产生生理效应。
SIRT1 is one of seven mammalian orthologs of yeast silent information regulator2 (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(CIPI/WAFI) 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.