BRD4 inhibition sensitizes cervical cancer to radiotherapy by attenuating DNA repair
BRD4 inhibition sensitizes cervical cancer to radiotherapy by attenuating DNA repair
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BRD4 抑制通过减弱 DNA 修复使宫颈癌对放射治疗敏感
DOI：
10.1038/s41388-021-01735-3
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发表时间：
2021-03-12
期刊：
影响因子：
8
通讯作者：
Wu, Xiaohua
中科院分区：
文献类型：
--
作者：
Ni, Mengdong;Li, Jiajia;Wu, Xiaohua
以顺铂为基础的放化疗是局部晚期宫颈癌的推荐治疗方案，但放射抵抗仍然是最重要和尚未解决的临床问题之一。研究表明，异常的表观遗传修饰是辐射抗性发生的主要原因之一。在这里，我们试图从表观遗传药物协同筛选中鉴定放射增敏剂，并探索其潜在机制。我们在宫颈癌细胞系中整合了表观遗传抑制剂和放射治疗，以确定潜在的放射增敏剂。进一步验证了该药物的致敏作用及其靶基因在体内外的功能。最后，我们在临床宫颈癌标本中验证了其靶基因的临床意义。我们确定BRD4抑制剂JQ1是一种有效的放射增敏剂。功能分析表明，抑制BRD4活性导致显著的放射增敏和增强宫颈癌细胞株的DNA损伤。通过使用RNA-seq检测JQ1介导的转录变化，我们确定RAD51AP1是参与辐射敏感性的主要BRD4靶基因。双荧光素酶报告实验和芯片定量聚合酶链式反应表明，BRD4与RAD51AP1的启动子区域结合并促进其转录，而BRD4的抑制作用减弱了该活性。体内实验也表明BRD4抑制和放射治疗之间存在协同作用。BRD4的高表达与预后和放射抵抗有关。BRD4抑制通过抑制RAD51AP1转录使宫颈癌对放射治疗敏感。JQ1联合放射治疗作为改善宫颈癌局部控制的治疗策略值得进一步评价。
Cisplatin-based chemoradiotherapy is the recommended treatment for local advanced cervical cancer, but radioresistance remains one of the most important and unresolved clinical problems. Investigations have revealed aberrant epigenetic modifications as one of the chief culprits for the development of radioresistance. Here, we attempt to identify a radiosensitizer from an epigenetic drug synergy screen and explore the underlying mechanism. We integrated epigenetic inhibitors and radiotherapy in cervical cancer cell lines to identify potential radiosensitizers. We further verified the sensitization effect of the drug and the function of its target gene both in vitro and in vivo. Finally, we validated the clinical significance of its target gene in clinical cervical cancer specimens. We identified JQ1, a BRD4 inhibitor, as a potent radiosensitizer. Functional assays demonstrated that repressing BRD4 activity led to significant radiosensitization and potentiation of DNA damage in cervical cancer cell lines. By using RNA-seq to determine JQ1-mediated changes in transcription, we identifiedRAD51AP1as a major BRD4 target gene involved in radiosensitivity. A dual-luciferase reporter assay and ChIP-qPCR showed that BRD4 binds to the promoter region ofRAD51AP1and promotes its transcription, whereas this activity was attenuated by BRD4 inhibition. The in vivo experiments also suggested a synergy between BRD4 inhibition and radiotherapy. High BRD4 expression was found to be related to a worse prognosis and radiation resistance. BRD4 inhibition sensitizes cervical cancer to radiotherapy by inhibitingRAD51AP1transcription. The combination of JQ1 with radiotherapy merits further evaluation as a therapeutic strategy for improving local control in cervical cancer.