SIRT2 通过调节 APC/C 的活性来维持基因组的完整性并抑制肿瘤发生。
SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity.
机构信息
Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
出版信息
Cancer Cell. 2011 Oct 18;20(4):487-99. doi: 10.1016/j.ccr.2011.09.004.
Abstract
Members of sirtuin family regulate multiple critical biological processes, yet their role in carcinogenesis remains controversial. To investigate the physiological functions of SIRT2 in development and tumorigenesis, we disrupted Sirt2 in mice. We demonstrated that SIRT2 regulates the anaphase-promoting complex/cyclosome activity through deacetylation of its coactivators, APC(CDH1) and CDC20. SIRT2 deficiency caused increased levels of mitotic regulators, including Aurora-A and -B that direct centrosome amplification, aneuploidy, and mitotic cell death. Sirt2-deficient mice develop gender-specific tumorigenesis, with females primarily developing mammary tumors, and males developing more hepatocellular carcinoma (HCC). Human breast cancers and HCC samples exhibited reduced SIRT2 levels compared with normal tissues. These data demonstrate that SIRT2 is a tumor suppressor through its role in regulating mitosis and genome integrity.
摘要
Sirtuin 家族成员调节多种关键的生物过程，但它们在致癌作用中的作用仍存在争议。为了研究 SIRT2 在发育和肿瘤发生中的生理功能，我们在小鼠中破坏了 Sirt2。我们证明 SIRT2 通过去乙酰化其共激活因子 APC（CDH1）和 CDC20 来调节后期促进复合物/环体活性。SIRT2 缺乏导致有丝分裂调节剂水平升高，包括指导中心体扩增、非整倍体和有丝分裂细胞死亡的 Aurora-A 和 -B。Sirt2 缺陷型小鼠表现出性别特异性的肿瘤发生，雌性主要发展为乳腺肿瘤，而雄性则发展为更多的肝细胞癌（HCC）。与正常组织相比，人类乳腺癌和 HCC 样本中的 SIRT2 水平降低。这些数据表明，SIRT2 是一种肿瘤抑制因子，通过其在调节有丝分裂和基因组完整性中的作用。
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