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

被引：47

作者：

Park, Jung-Hyun ^{[2
]}

Jong, Hyun-Soon ^{[2
,3
]}

Kim, Sang Gyun ^{[2
]}

Jung, Yeonjoo ^{[2
,3
]}

Lee, Keun-Wook ^{[1
,2
]}

Lee, Ju-Hee ^{[2
,3
]}

Kim, Dae-Kee ^{[4
]}

Bang, Yung-Jue ^{[1
,2
,3
]}

Kim, Tae-You ^{[1
,2
,3
]}

机构：

[1] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 110799, South Korea

[2] Seoul Natl Univ, Coll Med, Canc Res Inst, Natl Res Lab Canc Epigenet, Seoul 110799, South Korea

[3] Seoul Natl Univ, Coll Med, Dept Tumor Biol, Seoul 110799, South Korea

[4] In2Gen, Seoul, South Korea

来源：

JOURNAL OF MOLECULAR MEDICINE-JMM | 2008年 / 86卷 / 01期

关键词：

histone deacetylase inhibitor; Aurora-A; LAQ824; SK-7068;

D O I：

10.1007/s00109-007-0260-8

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：117 / 128

页数：12

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