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

HS Kim, A Vassilopoulos, RH Wang, T Lahusen, Z Xiao… - Cancer cell, 2011 - cell.com
HS Kim, A Vassilopoulos, RH Wang, T Lahusen, Z Xiao, X Xu, C Li, TD Veenstra, B Li, H Yu
Cancer cell, 2011cell.com
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 …
Summary
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, APCCDH1 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.
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