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

Cited 43 time in Web of Science Cited 41 time in Scopus
Authors
Park, Jung-Hyun; Jong, Hyun-Soon; Kim, Sang Gyun; Jung, Yeonjoo; Lee, Keun-Wook; Lee, Ju-Hee; Kim, Dae-Kee; Bang, Yung-Jue; Kim, Tae-You
Issue Date
2008-01
Publisher
Springer Verlag
Citation
Journal of Molecular Medicine, Vol.86 No.1, pp.117-128
Keywords
histone deacetylase inhibitorAurora-ALAQ824SK-7068
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.
ISSN
0946-2716
Language
English
URI
https://hdl.handle.net/10371/62183
DOI
https://doi.org/10.1007/s00109-007-0260-8
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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