Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors.
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 p21(Waf1/Cip1) expression was inhibited by EWS-Fli1 in EFTs. Histone deacetylase inhibitors (HDACIs) are known to up-regulate p21(Waf1/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 p21(Waf1/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.
Sakimura
Riku
R
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka City, Japan.
Tanaka
Kazuhiro
K
Nakatani
Fumihiko
F
Matsunobu
Tomoya
T
Li
Xu
X
Hanada
Masuo
M
Okada
Takamitsu
T
Nakamura
Tomoyuki
T
Matsumoto
Yoshihiro
Y
Iwamoto
Yukihide
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D018242:Neuroectodermal Tumors, Primitive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D016160:Retinoblastoma Protein; C087123:romidepsin