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Inhibitors of histone deacetylases induce tumor-selective cytotoxicity through modulating Aurora-A kinase.
- Source :
- Journal of Molecular Medicine; Jan2008, Vol. 86 Issue 1, p117-128, 12p, 1 Black and White Photograph, 5 Graphs
- Publication Year :
- 2008
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09462716
- Volume :
- 86
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Journal of Molecular Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 28329110
- Full Text :
- https://doi.org/10.1007/s00109-007-0260-8