Radiation-Induced CXCL12 Upregulation via Histone Modification at the Promoter in the Tumor Microenvironment of Hepatocellular Carcinoma
Radiation-Induced CXCL12 Upregulation via Histone Modification at the Promoter in the Tumor Microenvironment of Hepatocellular Carcinoma
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DOI：
10.14348/molcells.2019.2280
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发表时间：
2019-07-01
影响因子：
3.8
通讯作者：
Lee, Jong-Soo
中科院分区：
文献类型：
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作者：
Ahn, Hak Jun;Hwang, Soon Young;Lee, Jong-Soo
在电离辐射 (IR) 治疗过程中，肿瘤细胞可能会发生表观遗传变化。这些表观遗传变异可以影响 IR 反应并影响肿瘤的侵袭性。然而，IR 后组蛋白的表观遗传紊乱（与 IR 反应性有关）一直难以捉摸。在这里，我们研究了 IR 后改变的组蛋白修饰是否会影响辐射反应性。致癌性 CXCL12 mRNA 和蛋白在肝癌异位小鼠肿瘤微环境以及辐射后人肝癌 Huh7 和正常 IMR90 细胞共培养的残留癌细胞中表达更高。在其启动子区域，H3K4 甲基化也富集，而 H3K9 甲基化减少。因此，IR后侵袭性和侵袭性CD133(+)/CD24(-)细胞亚群增加。组蛋白去甲基酶抑制剂 IOX1 减弱 CXCL12 表达和恶性亚群，表明对 IR 的反应可以部分通过组蛋白修饰介导。综上所述，肝癌细胞中 CXCL12 启动子处辐射诱导的组蛋白改变与 CXCL12 上调和肿瘤微环境中侵袭性增加有关。
Tumor cells can vary epigenetically during ionizing irradiation (IR) treatment. These epigenetic variegations can influence IR response and shape tumor aggressiveness. However, epigenetic disturbance of histones after IR, implicating in IR responsiveness, has been elusive. Here, we investigate whether altered histone modification after IR can influence radiation responsiveness. The oncogenic CXCL12 mRNA and protein were more highly expressed in residual cancer cells from a hepatoma heterotopic murine tumor microenvironment and coculture of human hepatoma Huh7 and normal IMR90 cells after radiation. H3K4 methylation was also enriched and H3K9 methylation was decreased at its promoter region. Accordingly, invasiveness and the subpopulation of aggressive CD133(+)/CD24(-) cells increased after IR. Histone demethylase inhibitor IOX1 attenuated CXCL12 expression and the malignant subpopulation, suggesting that responses to IR can be partially mediated via histone modifications. Taken together, radiation-induced histone alterations at the CXCL12 promoter in hepatoma cells are linked to CXCL12 upregulation and increased aggressiveness in the tumor microenvironment.