S-Space College of Medicine/School of Medicine (의과대학/대학원) Program in Cancer Biology (협동과정-종양생물학전공) Journal Papers (저널논문_협동과정-종양생물학전공)
Inhibitors of histone deacetylases induce tumor-selective cytotoxicity through modulating Aurora-A kinase
- 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
- Springer Verlag
- J Mol Med. 2008 Jan;86(1):117-28. Epub 2007 Sep 13.
- Antineoplastic Agents; Biphenyl Compounds/pharmacology; Cell Death/drug effects; Cell Line, Tumor; Enzyme Inhibitors/*pharmacology; HSP70 Heat-Shock Proteins/metabolism; HSP90 Heat-Shock Proteins/metabolism; Histone Deacetylases/*antagonists & inhibitors; Humans; Hydroxamic Acids/pharmacology; Protein-Serine-Threonine Kinases/drug effects/*metabolism; Pyrrolidines/pharmacology; Stomach Neoplasms/drug therapy/pathology
- 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.
- 1432-1440 (Electronic)
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