Involvement of SIRT1 in hypoxic down-regulation of c-Myc and beta-catenin and hypoxic preconditioning effect of polyphenols.

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Hong KS, Park JI, Kim MJ, Kim HB, Lee JW, Dao TT, Oh WK, Kang CD, Kim SH

Involvement of SIRT1 in hypoxic down-regulation of c-Myc and beta-catenin and hypoxic preconditioning effect of polyphenols.

Toxicol Appl Pharmacol. 2012 Mar 1;259(2):210-8. doi: 10.1016/j.taap.2011.12.025. Epub 2012 Jan 5.

PubMed ID

22245592 [ View in PubMed

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Abstract

SIRT1 has been found to function as a Class III deacetylase that affects the acetylation status of histones and other important cellular nonhistone proteins involved in various cellular pathways including stress responses and apoptosis. In this study, we investigated the role of SIRT1 signaling in the hypoxic down-regulations of c-Myc and beta-catenin and hypoxic preconditioning effect of the red wine polyphenols such as piceatannol, myricetin, quercetin and resveratrol. We found that the expression of SIRT1 was significantly increased in hypoxia-exposed or hypoxic preconditioned HepG2 cells, which was closely associated with the up-regulation of HIF-1alpha and down-regulation of c-Myc and beta-catenin expression via deacetylation of these proteins. In addition, blockade of SIRT1 activation using siRNA or amurensin G, a new potent SIRT1 inhibitor, abolished hypoxia-induced HIF-1alpha expression but increased c-Myc and beta-catenin expression. SIRT1 was also found to stabilize HIF-1alpha protein and destabilize c-Myc, beta-catenin and PHD2 under hypoxia. We also found that myricetin, quercetin, piceatannol and resveratrol up-regulated HIF-1alpha and down-regulated c-Myc, PHD2 and beta-catenin expressions via SIRT1 activation, in a manner that mimics hypoxic preconditioning. This study provides new insights of the molecular mechanisms of hypoxic preconditioning and suggests that polyphenolic SIRT1 activators could be used to mimic hypoxic/ischemic preconditioning.