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SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress

Oncogene volume 26, pages 945–957 (2007)Cite this article

Abstract

We previously identified SIRT2, an nicotinamide adenine dinucleotide (NAD)-dependent tubulin deacetylase, as a protein downregulated in gliomas and glioma cell lines, which are characterized by aneuploidy. Other studies reported SIRT2 to be involved in mitotic progression in the normal cell cycle. We herein investigated whether SIRT2 functions in the mitotic checkpoint in response to mitotic stress caused by microtubule poisons. By monitoring chromosome condensation, the exogenously expressed SIRT2 was found to block the entry to chromosome condensation and subsequent hyperploid cell formation in glioma cell lines with a persistence of the cyclin B/cdc2 activity in response to mitotic stress. SIRT2 is thus a novel mitotic checkpoint protein that functions in the early metaphase to prevent chromosomal instability (CIN), characteristics previously reported for the CHFR protein. We further found that histone deacetylation, but not the aberrant DNA methylation of SIRT2 5′untranslated region is involved in the downregulation of SIRT2. Although SIRT2 is normally exclusively located in the cytoplasm, the rapid accumulation of SIRT2 in the nucleus was observed after treatment with a nuclear export inhibitor, leptomycin B and ionizing radiation in normal human fibroblasts, suggesting that nucleo-cytoplasmic shuttling regulates the SIRT2 function. Collectively, our results suggest that the further study of SIRT2 may thus provide new insights into the relationships among CIN, epigenetic regulation and tumorigenesis.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

5-Aza-dC:

5-aza-2′-deoxycytidine

ChIP:

chromatin immunoprecipitation

CIN:

chromosomal instability

EGFP:

enhanced green fluorescent protein

IR:

ionizing irradiation

TSA:

trichostatin A

LMB:

leptomycin B

NES:

nuclear export signal

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Acknowledgements

We thank S Abe (Tottori University) and Dr A Kurimasa (Tottori University) for technical assistance with the metaphase preparations and for valuable suggestions, respectively. We thank Cell Resource Center for Biomedical Research Institute of Development, Aging and Cancer (Tohoku University) for a kind gift of TIG-1 cells. This work was supported in part by grants from the Public Trust Haraguchi Memorial Cancer Research Fund (T. I.), the Ministry of Education, Culture, Sports, Science and Technology of Japan (T. I., M. H., M.O. and M. O.), and The 21st Century COE Program: The Research Core for Chromosome Engineering Technology (T. I. and M. O.).

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Authors and Affiliations

  1. Department of Human Genome Science, Graduate School of Medical Science, Tottori University, Yonago, Tottori, Japan

    T Inoue, M Hiratsuka, H Yamada, I Kishimoto, S Yamaguchi, S Nakano, M Katoh & M Oshimura

  2. Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Tottori, Japan

    M Osaki, H Yamada, I Kishimoto, S Yamaguchi, S Nakano & M Oshimura

  3. Division of Organ Pathology, Department of Microbiology and Pathology, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan

    M Osaki & H Ito

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  1. T Inoue
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Correspondence to M Oshimura.

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Inoue, T., Hiratsuka, M., Osaki, M. et al. SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress. Oncogene 26, 945–957 (2007). https://doi.org/10.1038/sj.onc.1209857

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