Disruption of Chromosomal Architecture of cox2 Locus Sensitizes Lung Cancer Cells to Radiotherapy.
Disruption of Chromosomal Architecture of cox2 Locus Sensitizes Lung Cancer Cells to Radiotherapy.
复制标题
cox2基因座染色体结构的破坏使肺癌细胞对放射治疗敏感
DOI：
10.1016/j.ymthe.2018.08.002
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发表时间：
2018-10-03
期刊：
影响因子：
--
通讯作者：
Wu L
中科院分区：
文献类型：
--
作者：
Sun Y;Dai H;Chen S;Zhang Y;Wu T;Cao X;Zhao G;Xu A;Wang J;Wu L
尽管使用放疗和化疗治疗肺癌，但肺癌患者的存活率仍然很低。先前的研究表明炎症因子如环氧合酶2（cox 2）的上调在肿瘤耐受中的重要性。本研究旨在探讨cox 2在肺癌放射敏感性中的作用。我们的研究结果表明，联合治疗的放射治疗与阿司匹林，抗炎药，诱导细胞存活的协同减少A549和H1299肺癌细胞。与正常人肺成纤维细胞（NHLFs）相比，A549细胞的细胞活力显著降低，凋亡水平显著增加。机制研究表明，阿司匹林在A549和H1299中减少cox 2是由于cox 2基因座的染色体结构被破坏所致。此外，染色质循环的破坏是由抑制p65的核转位和减少p65在cox2调控元件的富集介导的。重要的是，cox 2染色体结构的解体通过诱导凋亡触发了对γ辐射敏感的A549细胞。总之，我们提出了针对肺癌表观遗传调控的有效治疗方法和克服癌细胞辐射抗性的潜在策略的证据。Sun等人显示COX 2启动子和增强子之间染色质相互作用的破坏使肺癌细胞对放射疗法敏感，从而提供了克服肺癌细胞中放射抗性的潜在策略。
Despite treatment of lung cancer with radiotherapy and chemotherapy, the survival rate of lung cancer patients remains poor. Previous studies demonstrated the importance of upregulation of inflammatory factors, such as cyclooxygenase 2 (cox2), in tumor tolerance. In the present study, we investigated the role of cox2 in radiosensitivity of lung cancer. Our results showed that the combination treatment of radiation with aspirin, an anti-inflammatory drug, induced a synergistic reduction of cell survival in A549 and H1299 lung cancer cells. In comparison with normal human lung fibroblasts (NHLFs), the cell viability was significantly decreased and the level of apoptosis was remarkably enhanced in A549 cells. Mechanistic studies revealed that the reduction of cox2 by aspirin in A549 and H1299 was caused by disruption of the chromosomal architecture of the cox2 locus. Moreover, the disruption of chromatin looping was mediated by the inhibition of nuclear translocation of p65 and decreased enrichment of p65 at cox2-regulatory elements. Importantly, disorganization of the chromosomal architecture of cox2 triggered A549 cells sensitive to γ-radiation by the induction of apoptosis. In conclusion, we present evidence of an effective therapeutic treatment targeting the epigenetic regulation of lung cancer and a potential strategy to overcome radiation resistance in cancer cells. Sun et al. show that disruption of chromatin interaction between the cox2 promoter and enhancer sensitizes lung cancer cells to radiotherapy, thereby providing a potential strategy to overcome radiation resistance in lung cancer cells.
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功能表达克隆将COX-2鉴定为抗原特异性癌症免疫的抑制剂。
影响因子：
9
作者：
Göbel C;Breitenbuecher F;Kalkavan H;Hähnel PS;Kasper S;Hoffarth S;Merches K;Schild H;Lang KS;Schuler M
通讯作者：
Schuler M
影响因子：
7.2
作者：
Kanarek, Naama;London, Nir;Ben-Neriah, Yinon
通讯作者：
Ben-Neriah, Yinon
影响因子：
14.9
作者：
Gong F;Sun L;Wang Z;Shi J;Li W;Wang S;Han X;Sun Y
通讯作者：
Sun Y
影响因子：
5.8
作者：
Hopper-Borge EA;Nasto RE;Ratushny V;Weiner LM;Golemis EA;Astsaturov I
通讯作者：
Astsaturov I
影响因子：
11.4
作者：
Han, JA;Kim, JI;Lee, SW
通讯作者：
Lee, SW