SIRT2 Maintains Genome Integrity and Suppresses Tumorigenesis through Regulating APC/C Activity

被引：478

作者：

Kim, Hyun-Seok ^{[1
,5
,6
,7
]}

Vassilopoulos, Athanassios ^{[1
]}

Wang, Rui-Hong ^{[1
]}

Lahusen, Tyler ^{[1
]}

Xiao, Zhen ^{[3
]}

Xu, Xiaoling ^{[1
]}

Li, Cuiling ^{[1
]}

Veenstra, Timothy D. ^{[3
]}

Li, Bing ^{[4
]}

Yu, Hongtao ^{[4
]}

Ji, Junfang ^{[2
]}

Wang, Xin Wei ^{[2
]}

Park, Seong-Hoon ^{[5
,6
,7
]}

Cha, Yong I. ^{[5
,6
,7
]}

Gius, David ^{[5
,6
,7
]}

Deng, Chu-Xia ^{[1
]}

机构：

[1] Natl Inst Diabet Digest & Kidney Dis, Genet Dev & Dis Branch, Bethesda, MD 20892 USA

[2] NCI, Lab Human Carcinogenesis, NIH, Bethesda, MD 20892 USA

[3] NCI Frederick, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick, Frederick, MD 20170 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA

[5] Vanderbilt Univ, Med Ctr, Dept Canc Biol, Nashville, TN 37232 USA

[6] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA

[7] Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, Nashville, TN 37232 USA

来源：

CANCER CELL | 2011年 / 20卷 / 04期

基金：

美国国家卫生研究院;

关键词：

ANAPHASE-PROMOTING COMPLEX; SPINDLE ASSEMBLY CHECKPOINT; TUMOR AMPLIFIED KINASE; AURORA-A; HEPATOCELLULAR-CARCINOMA; CELL-CYCLE; CENTROSOME AMPLIFICATION; TUBULIN DEACETYLASE; GENETIC INSTABILITY; MAMMALIAN SIRTUINS;

D O I：

10.1016/j.ccr.2011.09.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：487 / 499

页数：13

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