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.
Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Hyun-Seok
HS
Kim
Athanassios
A
Vassilopoulos
Rui-Hong
RH
Wang
Tyler
T
Lahusen
Zhen
Z
Xiao
Xiaoling
X
Xu
Cuiling
C
Li
Timothy D
TD
Veenstra
Bing
B
Li
Hongtao
H
Yu
Junfang
J
Ji
Xin Wei
XW
Wang
Seong-Hoon
SH
Park
Yong I
YI
Cha
David
D
Gius
Chu-Xia
CX
Deng
D000107:Acetylation; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001943:Breast Neoplasms / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D064199:Cdc20 Proteins; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D020090:Chromosome Segregation / Q000235:genetics; D005260:Female; D042822:Genomic Instability; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000235:genetics; D051379:Mice; D008938:Mitosis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012737:Sex Factors; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism / Q000502:physiology
D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; C577585:Fzr1 protein, mouse; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2