Histone deacetylase inhibitors enhance phosphorylation of histone H2AX after ionizing radiation
Histone deacetylase inhibitors enhance phosphorylation of histone H2AX after ionizing radiation
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DOI：
10.1016/j.ijrobp.2006.03.019
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发表时间：
2006-07-01
影响因子：
7
通讯作者：
Shinomura, Yasuhisa
中科院分区：
文献类型：
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作者：
Zhang, Yubin;Adachi, Masaaki;Shinomura, Yasuhisa
本研究采用摄动法、Edgeworth级数、可靠性优化、可靠性敏感性技术和鲁棒设计，为在已知原始随机变量前四矩的情况下，任意分布参数的车辆部件的鲁棒可靠性设计提供了一种实用有效的方法。得到了具有任意分布参数的车辆部件鲁棒可靠性设计的理论公式。将可靠性敏感性添加到可靠性优化设计模型中，将鲁棒可靠性设计描述为多目标优化。在已知原始随机变量的前四矩的情况下，利用相应的程序可以准确、快速地获得具有任意分布参数的车辆部件的鲁棒可靠性设计参数。 目的：组蛋白脱乙酰酶（HDAC）抑制剂被认为是一种有前途的放射增敏剂。为了探讨它们对电离辐射 (IR) 的影响，我们检查了 HDAC 抑制剂间羧基肉桂酸双羟基酰胺 (CBHA) 和缩酚肽 FK228 是否影响 H2AX 磷酸化 (gamma-H2AX)，这是 IR 暴露后 DNA 双链断裂的标志。方法和材料：我们评估了 HDAC 抑制剂的效果 人肺癌 A549 细胞的克隆形成分析和 A549 异种移植肿瘤的进展。通过组蛋白 gamma-H2AX 评估 IR 诱导的 DNA 损伤。通过组蛋白乙酰转移酶 p300 的过表达诱导组蛋白过度乙酰化，并通过蛋白质印迹进行评估。结果：M-羧基肉桂酸双羟基酰胺预处理使 A549 细胞放射增敏，并强烈抑制 A549 异种移植肿瘤的进展。 CBHA 和 FK228（但不是 5-氟尿嘧啶）增强了 A549 和其他癌细胞系中 IR 诱导的 γ-H2AX。 p300 的过度表达同样会增强 IR 诱导的 γ-H2AX。结论：本研究的结果表明，HDAC 抑制剂很可能通过组蛋白高度乙酰化增强 IR 诱导的 γ-H2AX，并对各种癌症进行放射增敏。 (c) 2006 爱思唯尔公司
This study employed the perturbation method, the Edgeworth series, the reliability optimization, the reliability sensitivity technique and the robust design to present a practical and effective approach for the robust reliability design of vehicle components with arbitrary distribution parameters on the condition of known first four moments of original random variables. The theoretical formulae of the robust reliability design for vehicle components with arbitrary distribution parameters are obtained. The reliability sensitivity is added to the reliability optimization design model and the robust reliability design is described as a multi-objection optimization. On the condition of known first four moments of original random variables, the respective program can be used to obtain the robust reliability design parameters of vehicle components with arbitrary distribution parameters accurately and quickly.Purpose: Histone deacetylase (HDAC) inhibitors are believed to be promising radiosensitizers. To explore their effects on ionizing radiation (IR), we examined whether the HDAC inhibitors m-carboxycinnamic acid bis-hydroxamide (CBHA) and depsipeptide FK228 affect H2AX phosphorylation (gamma-H2AX), a landmark of DNA double-strand breaks after IR exposure.Methods and Materials: We evaluated the effects of the HDAC inhibitors on clonogenic assay in human lung carcinoma A549 cells and progression of A549 xenograft tumors. IR-induced DNA damage was evaluated by histone gamma-H2AX. Histone hyperacetylation was induced by overexpression of histone acetyltransferase p300 and evaluated by Western blots.Results: M-carboxycinnamic acid bishydroxyamide pretreatment radiosensitized A549 cells and strongly inhibited A549 xenograft tumor progression. CBHA and FK228, but not 5-fluorouracil, enhanced IR-induced gamma-H2AX in A549 and other cancer cell lines. Overexpression of p300 similarly augmented IR-induced gamma-H2AX.Conclusion: The results of this study suggest that HDAC inhibitors enhance IR-induced gamma-H2AX, most likely through histone hyperacetylation, and radiosensitize various cancers. (c) 2006 Elsevier Inc.