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 journalArticle

316 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, 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.

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Kim, H. S., Vassilopoulos, A., Wang, R. H., Lahusen, T., Xiao, Z., Xu, X., Li, C., Veenstra, T. D., Li, B., Yu, H., Ji, J., Wang, X. W., Park, S. H., Cha, Y. I., Gius, D., & Deng, C. X. (2011). SIRT2 Maintains Genome Integrity and Suppresses Tumorigenesis through Regulating APC/C Activity. Cancer Cell, 20(4), 487-499. https://doi.org/10.1016/j.ccr.2011.09.004