SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation
  • Anaphase-Promoting Complex-Cyclosome
  • Animals
  • Aurora Kinase A
  • Aurora Kinases
  • Breast Neoplasms / genetics
  • Carcinoma, Hepatocellular / genetics
  • Cdc20 Proteins
  • Cdh1 Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Transformation, Neoplastic / genetics*
  • Chromosome Segregation / genetics
  • Female
  • Genomic Instability
  • Humans
  • Liver Neoplasms / genetics
  • Male
  • Mammary Neoplasms, Animal / genetics
  • Mice
  • Mitosis / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Sex Factors
  • Sirtuin 2 / genetics
  • Sirtuin 2 / metabolism
  • Sirtuin 2 / physiology*
  • Ubiquitin-Protein Ligase Complexes / metabolism
  • Ubiquitin-Protein Ligase Complexes / physiology

Substances

  • Cdc20 Proteins
  • Cdc20 protein, mouse
  • Cdh1 Proteins
  • Cell Cycle Proteins
  • Fzr1 protein, mouse
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome
  • Aurka protein, mouse
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Sirt2 protein, mouse
  • Sirtuin 2