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Inhibitors of histone deacetylases induce tumor-selective cytotoxicity through modulating Aurora-A kinase

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Abstract

The molecular basis of the antitumor selectivity of histone deacetylase inhibitors (HDIs) remains unclear. Centrosomal Aurora-A kinase regulates chromosomal segregation during mitosis. The overexpression or amplification of Aurora-A leads to genetic instability, and its inhibition has shown significant antitumor effects. In this paper, we report that structurally related hydroxamate LAQ824 and SK-7068 induce tumor-selective mitotic defects by depleting Aurora-A. We found that HDI-treated cancer cells, unlike nontransformed cells, exhibit defective mitotic spindles. After HDI, Aurora-A was selectively downregulated in cancer cells, whereas Aurora-B remained unchanged in both cancer and nontransformed cells. LAQ824 or SK-7068 treatment inhibited histone deacetylase (HDAC) 6 present in Aurora-A/heat shock protein (Hsp) 90 complex. Inhibition of HDAC6 acetylated Hsp90 and resulted in dissociation of acetylated Hsp90 from Aurora-A. As a result, Hsp70 binding to Aurora-A was enhanced in cancer cells, leading to proteasomal degradation of Aurora-A. Overall, these provide a novel molecular basis of tumor selectivity of HDI. LAQ824 and SK-7068 might be more effective HDIs in cancer cells with Aurora-A overexpression.

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Acknowledgments

We thank Kyung-Sun Kang for the M13SV1 cells and Keith Robertson for reviewing this manuscript. We also thank the members of Dr. Bang’s laboratory for helpful discussion. This work was supported by the Korean Ministry of Science and Technology through the National Research Laboratory Program for Cancer Epigenetics and in part by the Cancer Research Institute, Seoul National University College of Medicine (Grant no. CRI-03-05).

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Authors and Affiliations

  1. National Research Laboratory for Cancer Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea

    Jung-Hyun Park, Hyun-Soon Jong, Sang Gyun Kim, Yeonjoo Jung, Keun-Wook Lee, Ju-Hee Lee, Yung-Jue Bang & Tae-You Kim

  2. Department of Tumor Biology, Seoul National University College of Medicine, Seoul, South Korea

    Hyun-Soon Jong, Yeonjoo Jung, Ju-Hee Lee, Yung-Jue Bang & Tae-You Kim

  3. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 110-799, South Korea

    Keun-Wook Lee, Yung-Jue Bang & Tae-You Kim

  4. In2Gen, Seoul, South Korea

    Dae-Kee Kim

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Park, JH., Jong, HS., Kim, S.G. et al. Inhibitors of histone deacetylases induce tumor-selective cytotoxicity through modulating Aurora-A kinase. J Mol Med 86, 117–128 (2008). https://doi.org/10.1007/s00109-007-0260-8

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