Boily G, He X H, Pearce B, Jardine K, McBurney M W
Center for Cancer Therapeutics, Ottawa Health Research Institute, and Department of Medicine, University of Ottawa, Ontario, Canada.
Oncogene. 2009 Aug 13;28(32):2882-93. doi: 10.1038/onc.2009.147. Epub 2009 Jun 8.
The function of the class III histone deacetylase, Sir2, in promoting lifespan extension is well established in small model organisms. By analogy, SirT1, the mammalian orthologue of Sir2, is a candidate gene to slow down aging and forestall the onset of age-associated diseases. We have used SirT1-null mice to study the function of SirT1 in susceptibility to tumorigenesis. The number of intestinal polyps induced in mice carrying the Apc(min) mutation was unaffected by the SirT1 genotype although the average polyp size was slightly smaller in the SirT1-null animals. Similarly, the presence or absence of SirT1 had no effect on incidence and tumor load of skin papillomas induced by the classical two-stage carcinogenesis protocol. We found that resveratrol topically applied to the skin profoundly reduced tumorigenesis. This chemoprotective effect was significantly reduced but not ablated in SirT1-null mice, suggesting that part of the protection afforded by resveratrol requires the SirT1-encoded protein. Thus, our results suggest that SirT1 does not behave like a classical tumor-suppressor gene but the antitumor activity of resveratrol is mediated at least in part by SirT1.
III类组蛋白去乙酰化酶Sir2在促进小型模式生物寿命延长方面的功能已得到充分证实。类似地，Sir2在哺乳动物中的同源物SirT1是一个可能减缓衰老并预防与年龄相关疾病发生的候选基因。我们利用SirT1基因敲除小鼠研究SirT1在肿瘤发生易感性中的功能。携带Apc(min)突变的小鼠肠道息肉数量不受SirT1基因型影响，尽管SirT1基因敲除动物的息肉平均大小略小。同样，SirT1的有无对经典两阶段致癌方案诱导的皮肤乳头状瘤的发生率和肿瘤负荷没有影响。我们发现局部应用于皮肤的白藜芦醇能显著降低肿瘤发生。在SirT1基因敲除小鼠中，这种化学保护作用虽显著降低但并未消除，这表明白藜芦醇提供的部分保护需要SirT1编码的蛋白质。因此，我们的结果表明SirT1的行为不像经典的肿瘤抑制基因，但白藜芦醇的抗肿瘤活性至少部分是由SirT1介导的。
