The processes mediating the repair of DNA double-strand breaks (DSB) are critical determinants of radiosensitivity and provide a source of potential targets for tumor radiosensitization. Among the events required for efficient DSB repair are a variety of post-translational histone modifications, including methylation. Because trimethylation of histone H3 on lysine 27 (H3K27me3) has been associated with chromatin condensation, which can influence DSB repair, we determined the effects of radiation on H3K27me3 levels in tumor and normal cell lines. Irradiation of tumor cells resulted in a rapid loss of H3K27me3, which was prevented by the siRNA-mediated knockdown of the H3K27 demethylase UTX. Knockdown of UTX also enhanced the radiosensitivity of each tumor cell line. Treatment of tumor cells with the H3K27 demethylase inhibitor GSKJ4 immediately before irradiation prevented the radiation-induced decrease in H3K27me3 and enhanced radiosensitivity. As determined by neutral comet analysis and γH2AX expression, this GSKJ4 treatment protocol inhibited the repair of radiation-induced DSBs. Consistent with in vitro results, treatment of mice bearing leg tumor xenografts with GSKJ4 significantly enhance radiation-induce tumor growth delay. In contrast with results generated from tumor cell lines, radiation had no effect on H3K27me3 levels in normal fibroblast cell lines and GSKJ4 did not enhance their radiosensitivity. These data suggest that H3K27me3 demethylation contributes to DSB repair in tumor cells and that UTX, the demethylase responsible, provides a target for selective tumor cell radiosensitization. Mol Cancer Ther; 17(5); 1070–8. ©2018 AACR.

中文翻译：

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抑制组蛋白 H3K27 去甲基化酶 UTX 可增强肿瘤细胞的放射敏感性

介导 DNA 双链断裂 (DSB) 修复的过程是放射敏感性的关键决定因素，并为肿瘤放射增敏提供了潜在靶标的来源。有效的 DSB 修复所需的事件包括各种翻译后组蛋白修饰，包括甲基化。由于赖氨酸 27 (H3K27me3) 上组蛋白 H3 的三甲基化与染色质凝聚有关，这会影响 DSB 修复，我们确定了辐射对肿瘤和正常细胞系中 H3K27me3 水平的影响。肿瘤细胞的辐照导致 H3K27me3 的快速丢失，这被 siRNA 介导的 H3K27 脱甲基酶 UTX 的敲低所阻止。敲除 UTX 还增强了每个肿瘤细胞系的放射敏感性。在照射前立即用 H3K27 去甲基化酶抑制剂 GSKJ4 处理肿瘤细胞可防止辐射诱导的 H3K27me3 减少并增强放射敏感性。根据中性彗星分析和 γH2AX 表达确定，这种 GSKJ4 治疗方案抑制了辐射诱导的 DSB 的修复。与体外结果一致，用 GSKJ4 治疗携带腿部肿瘤异种移植物的小鼠显着增强了辐射诱导的肿瘤生长延迟。与从肿瘤细胞系产生的结果相反，辐射对正常成纤维细胞系中的 H3K27me3 水平没有影响，GSKJ4 没有增强它们的放射敏感性。这些数据表明 H3K27me3 去甲基化有助于肿瘤细胞中的 DSB 修复，并且负责去甲基化酶 UTX 为选择性肿瘤细胞放射增敏提供了靶点。摩尔癌症治疗; 17(5); 1070-8。©2018 AACR。