Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors
Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors
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DOI：
10.1002/ijc.21069
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发表时间：
2005-09-20
影响因子：
6.4
通讯作者：
Iwamoto, Y
中科院分区：
文献类型：
--
作者：
Sakimura, R;Tanaka, K;Iwamoto, Y
在大多数尤文家族肿瘤（EFT）中鉴定的嵌合蛋白EWS-Fli 1已被证明与EFT的致瘤性相关。我们以前曾报道，p21（Waf 1/Cip 1）的表达抑制EWS-Fli 1在EFTs。已知组蛋白去乙酰化酶抑制剂（HDACIs）在各种细胞中上调p21（Waf 1/Cip 1）表达，并显示出作为癌症治疗的前景。在这里，我们证明了EWS-Fli 1可能参与组蛋白乙酰化和去乙酰化的活动，以及HDACIs作为EFT的抗肿瘤剂的潜在用途。一种新的HDACI，FK 228，强烈诱导p21（Waf 1/Cip 1）的表达，导致视网膜母细胞瘤蛋白（Rb）在EFT细胞中的低磷酸化。结果表明，EWS-Fli 1通过抑制组蛋白乙酰转移酶（HAT）和增强组蛋白去乙酰化酶（HDAC）活性来下调EFT细胞组蛋白乙酰化。FK 228处理阻断了EWS-Fli 1的这两种异常功能。HDACIs还抑制EWS-Fli 1蛋白和mRNA的表达。我们认为HDACIs可能通过抑制EWS启动子活性来抑制EWS-Fli 1的表达。FK 228在纳摩尔浓度下对EFT细胞表现出强效的生长抑制作用，以及EFT和正常细胞之间的凋亡作用的明显区别。此外，腹膜内给予FK 228在体内显著抑制肿瘤生长并诱导EFT细胞凋亡。这些结果表明，HDACI可能是一个很有前途的试剂，用于基于分子的化疗对EFT。(c)2005 Wiley-Liss，Inc.
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. (c) 2005 Wiley-Liss, Inc.