A novel chalcone polyphenol inhibits the deacetylase activity of SIRT1 and cell growth in HEK293T cells.
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 p21CIP1/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.
Kahyo
Tomoaki
T
Mitsubishi Kagaku Institute of Life Sciences (MITILS), Machida, Tokyo, Japan. aynoken@mitils.jp
Ichikawa
Shuji
S
Hatanaka
Takahiro
T
Yamada
Maki K
MK
Setou
Mitsutoshi
M
D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D009284:Naphthols / Q000494:pharmacology; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; C493956:CDKN1A protein, human; D047188:Chalcones; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D009284:Naphthols; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C439060:sirtinol; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins