SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity.
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.
Mesh Terms:
Acetylation, Animals, Breast Neoplasms, Carcinoma, Hepatocellular, Cell Cycle Proteins, Cell Transformation, Neoplastic, Chromosome Segregation, Female, Genomic Instability, Humans, Liver Neoplasms, Male, Mammary Neoplasms, Animal, Mice, Mitosis, Protein-Serine-Threonine Kinases, Sex Factors, Sirtuin 2, Ubiquitin-Protein Ligase Complexes
Acetylation, Animals, Breast Neoplasms, Carcinoma, Hepatocellular, Cell Cycle Proteins, Cell Transformation, Neoplastic, Chromosome Segregation, Female, Genomic Instability, Humans, Liver Neoplasms, Male, Mammary Neoplasms, Animal, Mice, Mitosis, Protein-Serine-Threonine Kinases, Sex Factors, Sirtuin 2, Ubiquitin-Protein Ligase Complexes
Cancer Cell
Date: Oct. 18, 2011
PubMed ID: 22014574
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