BACKGROUND Poor-responsiveness of tumors to radiotherapy is a major clinical problem. Owing to the dynamic nature of the epigenome, the identification and targeting of potential epigenetic modifiers may be helpful to curb radio-resistance. This requires a detailed exploration of the epigenetic changes that occur during the acquirement of radio-resistance. Such an understanding can be applied for effective utilization of treatment adjuncts to enhance the efficacy of radiotherapy and reduce the incidence of tumor recurrence. RESULTS This study explored the epigenetic alterations that occur during the acquirement of radio-resistance. Sequential irradiation of MCF7 breast cancer cell line up to 20 Gy generated a radio-resistant model. Micrococcal nuclease digestion demonstrated the presence of compact chromatin architecture coupled with decreased levels of histone PTMs H3K9ac, H3K27 ac, and H3S10pK14ac in the G0/G1 and mitotic cell cycle phases of the radio-resistant cells. Further investigation revealed that the radio-resistant population possessed high HDAC and low HAT activity, thus making them suitable candidates for HDAC inhibitor-based radio-sensitization. Treatment of radio-resistant cells with HDAC inhibitor valproic acid led to the retention of γH2AX and decreased H3S10p after irradiation. Additionally, an analysis of 38 human patient samples obtained from 8 different tumor types showed variable tumor HDAC activity, thus demonstrating inter-tumoral epigenetic heterogeneity in a patient population. CONCLUSION The study revealed that an imbalance of HAT and HDAC activities led to the loss of site-specific histone acetylation and chromatin compaction as breast cancer cells acquired radio-resistance. Due to variation in the tumor HDAC activity among patients, our report suggests performing a prior assessment of the tumor epigenome to maximize the benefit of HDAC inhibitor-based radio-sensitization.

中文翻译：

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HDAC活性升高和组蛋白磷酸乙酰化改变，使乳腺癌细胞获得了抗辐射表型。

背景技术肿瘤对放射疗法的不良反应是主要的临床问题。由于表观基因组的动态性质，潜在表观遗传修饰子的鉴定和靶向可能有助于抑制抗辐射性。这需要对在获得抗辐射性过程中发生的表观遗传学变化进行详细研究。这样的理解可以被用于有效地利用治疗辅助剂以增强放射治疗的效力并减少肿瘤复发的发生率。结果本研究探讨了在获得抗辐射性过程中发生的表观遗传学变化。依次照射高达20 Gy的MCF7乳腺癌细胞系产生了抗辐射模型。微球菌核酸酶消化法表明，紧密染色质结构的存在，以及抗辐射细胞的G0 / G1和有丝分裂细胞周期阶段中的组蛋白PTM H3K9ac，H3K27 ac和H3S10pK14ac含量降低。进一步的研究表明，抗辐射人群具有高HDAC和低HAT活性，因此使其适合基于HDAC抑制剂的放射敏化。用HDAC抑制剂丙戊酸处理抗辐射细胞可导致γH2AX保留并在辐射后降低H3S10p。此外，对从8种不同肿瘤类型中获得的38个人类患者样品的分析显示，肿瘤HDAC活性可变，因此证明了患者群体中肿瘤间表观遗传异质性。结论该研究表明，由于乳腺癌细胞获得了抗辐射性，HAT和HDAC活性的失衡导致位点特异性组蛋白乙酰化和染色质紧实度的丧失。由于患者中肿瘤HDAC活性的差异，我们的报告建议对肿瘤表观基因组进行事先评估，以最大化基于HDAC抑制剂的放射增敏作用。