Division of Human Genome Science, Department of Molecular and Cellular Biology, School of Life Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
Genes Cells. 2011 Jan;16(1):34-45. doi: 10.1111/j.1365-2443.2010.01460.x. Epub 2010 Nov 9.
We previously reported that sirtuin 2 (SIRT2), a mammalian member of the NAD+-dependent protein deacetylases, participates in mitotic regulation, specifically, in efficient mitotic cell death caused by the spindle checkpoint. Here, we describe a novel function of SIRT2 that is different from mitotic regulation. SIRT2 down-regulation using siRNA caused apoptosis in cancer cell lines such as HeLa cells, but not in normal cells. The apoptosis was caused by p53 accumulation, which is mediated by p38 MAPK activation-dependent degradation of p300 and the subsequent MDM2 degradation. Sirtuin inhibitors are emerging as antitumor drugs, and this function has been ascribed to the inhibition of SIRT1, the most well-characterized sirtuin that deacetylases p53 to promote cell survival and also binds to other proteins in response to genotoxic stress. This study suggests that SIRT2 can be a novel molecular target for cancer therapy and provides a molecular basis for the efficacy of SIRT2 for future cancer therapy.
我们之前曾报道过，组蛋白去乙酰化酶 SIRT2 是 NAD+依赖的蛋白去乙酰化酶中的哺乳动物成员，它参与有丝分裂调控，特别是纺锤体检验点引起的有效有丝分裂细胞死亡。在这里，我们描述了 SIRT2 的一个不同于有丝分裂调控的新功能。用 siRNA 下调 SIRT2 会导致 HeLa 等癌细胞系发生细胞凋亡，但不会导致正常细胞发生凋亡。凋亡是由 p53 积累引起的，这是由 p38 MAPK 激活依赖性降解 p300 和随后的 MDM2 降解介导的。Sirtuin 抑制剂作为抗肿瘤药物正在出现，这种功能归因于 SIRT1 的抑制，SIRT1 是最具特征性的去乙酰化酶 p53，以促进细胞存活，并且也结合其他蛋白质以响应遗传毒性应激。本研究表明，SIRT2 可以成为癌症治疗的一个新的分子靶点，并为 SIRT2 在未来癌症治疗中的疗效提供了分子基础。
