Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors
Version of Record online: 22 APR 2005
Copyright © 2005 Wiley-Liss, Inc.
International Journal of Cancer
Volume 116, Issue 5, pages 784–792, 20 September 2005
How to Cite
Sakimura, R., Tanaka, K., Nakatani, F., Matsunobu, T., Li, X., Hanada, M., Okada, T., Nakamura, T., Matsumoto, Y. and Iwamoto, Y. (2005), Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors. Int. J. Cancer, 116: 784–792. doi: 10.1002/ijc.21069
- Issue online: 20 JUL 2005
- Version of Record online: 22 APR 2005
- Manuscript Accepted: 4 FEB 2005
- Manuscript Received: 6 OCT 2004
- Scientific Research, Japan Society for the Promotion of Science. Grant Numbers: 14207057, 15591586
- Cancer Research on Priority Areas, Ministry of Education, Science, Sports and Culture, Japan. Grant Number: 16023248
- Japan Society for the Promotion of Science Fujita Memorial Fund for Medical Research
- HDAC inhibitor;
A chimeric protein, EWS-Fli1, identified in most Ewing's family tumors (EFTs) has been shown to be associated with the tumorigenicity of EFTs. We have previously reported that p21Waf1/Cip1 expression was inhibited by EWS-Fli1 in EFTs. Histone deacetylase inhibitors (HDACIs) are known to up-regulate p21Waf1/Cip1 expression in various cells and show promise as a cancer therapy. Here, we demonstrate the possible involvement of EWS-Fli1 in the activities of both histone acetylation and deacetylation, as well as the potential use of HDACIs as an antitumor agent for EFTs. A novel HDACI, FK228, strongly induced p21Waf1/Cip1 expression, leading to the hypophosphorylation of retinoblastoma protein (Rb) in EFT cells. Results indicated that EWS-Fli1 deregulated histone acetylation through both the repression of histone acetyltransferase (HAT) and the enhancement of histone deacetylase (HDAC) activities in EFT cells. FK228 treatment blocked both of the abnormal functions of EWS-Fli1. Expressions of EWS-Fli1 protein and mRNA were also inhibited by HDACIs. We suggest that HDACIs might inhibit the expression of EWS-Fli1 via the suppression of the EWS promoter activity. FK228 demonstrated potent growth inhibitory effects on EFT cells at nanomolar concentrations, as well as an apparent distinction in the apoptotic effects between EFT and normal cells. Moreover, intraperitoneal administration of FK228 significantly inhibited tumor growth and induced apoptosis in EFTs in vivo. These results suggest that HDACI might be a promising reagent for use in molecular-based chemotherapy against EFTs. © 2005 Wiley-Liss, Inc.