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

Hyun Seok Kim, Athanassios Vassilopoulos, Rui Hong Wang, Tyler Lahusen, Zhen Xiao, Xiaoling Xu, Cuiling Li, Timothy D. Veenstra, Bing Li, Hongtao Yu, Junfang Ji, Xin Wei Wang, Seong Hoon Park, Yong I. Cha, David Gius, Chu Xia Deng

Research output: Contribution to journalArticlepeer-review

444 Scopus citations

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, 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.

Original languageEnglish
Pages (from-to)487-499
Number of pages13
JournalCancer Cell
Volume20
Issue number4
DOIs
StatePublished - 18 Oct 2011

Bibliographical note

Funding Information:
We thank members of Dr. Deng's lab for their critical discussion of this work. This research was supported (in part) by the Intramural Research Program of the NIDDK, NCI, and CCR, NIH. D.G. is supported by 1R01CA152601-01 and 1R01CA152799-01 from the NCI, BC093803 from the DOD, and SPORE P50CA98131. This project was also supported with federal funds from the National Cancer Institute, National Institutes of Health, DHHS, in part under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organization imply endorsement by the U.S. government. All investigators have no research conflict.

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