INSERM, UMR_S1256, NGERE (Nutrition, Genetics, and Environmental Risk Exposure), Faculty of Medicine of Nancy, University of Lorraine, 9 Avenue de la Forêt de Haye, 54000, Vandoeuvre-lès-Nancy, Nancy, France.
Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, 54000, Vandoeuvre-lès-Nancy, France.
Clin Epigenetics. 2021 Dec 1;13(1):212. doi: 10.1186/s13148-021-01199-y.
Although radiation therapy represents a core cancer treatment modality, its efficacy is hampered by radioresistance. The effect of ionizing radiations (IRs) is well known regarding their ability to induce genetic alterations; however, their impact on the epigenome landscape in cancer, notably at the CpG dinucleotide resolution, remains to be further deciphered. In addition, no evidence is available regarding the effect of IRs on the DNA methylome profile according to the methionine dependency phenotype, which represents a hallmark of metabolic adaptation in cancer.
We used a case-control study design with a fractionated irradiation regimen on four cancerous cell lines representative of HCC (HepG2), melanoma (MeWo and MeWo-LC1, which exhibit opposed methionine dependency phenotypes), and glioblastoma (U251). We performed high-resolution genome-wide DNA methylome profiling using the MethylationEPIC BeadChip on baseline conditions, irradiated cell lines (cumulative dose of 10 Gy), and non-irradiated counterparts. We performed epigenome-wide association studies to assess the effect of IRs and methionine-dependency-oriented analysis by carrying out epigenome-wide conditional logistic regression. We looked for epigenome signatures at the locus and single-probe (CpG dinucleotide) levels and through enrichment analyses of gene ontologies (GO). The EpiMet project was registered under the ID#AAP-BMS_003_211.
EWASs revealed shared GO annotation pathways associated with increased methylation signatures for several biological processes in response to IRs, including blood circulation, plasma membrane-bounded cell projection organization, cell projection organization, multicellular organismal process, developmental process, and animal organ morphogenesis. Epigenome-wide conditional logistic regression analysis on the methionine dependency phenotype highlighted several epigenome signatures related to cell cycle and division and responses to IR and ultraviolet light.
IRs generated a variation in the methylation level of a high number of CpG probes with shared biological pathways, including those associated with cell cycle and division, responses to IRs, sustained angiogenesis, tissue invasion, and metastasis. These results provide insight on shared adaptive mechanisms of the epigenome in cancerous cell lines in response to IR. Future experiments should focus on the tryptic association between IRs, the initiation of a radioresistance phenotype, and their interaction with methionine dependency as a hallmark of metabolic adaptation in cancer.
尽管放射治疗是癌症的核心治疗方式之一，但它的疗效受到放射抗性的限制。电离辐射（IRs）的作用众所周知，它们能够诱导遗传改变；然而，它们对癌症表观基因组景观的影响，特别是在 CpG 二核苷酸分辨率方面，仍有待进一步阐明。此外，根据代表癌症代谢适应特征的蛋氨酸依赖性表型，尚没有关于 IRs 对 DNA 甲基化组谱影响的证据。
我们使用了一种病例对照研究设计，对四种具有代表性的肝癌（HepG2）、黑色素瘤（MeWo 和 MeWo-LC1，它们表现出相反的蛋氨酸依赖性表型）和神经胶质瘤（U251）的癌细胞系进行了分次照射方案。我们使用 MethylationEPIC BeadChip 在基线条件、照射细胞系（累积剂量为 10 Gy）和未照射对照物上进行了全基因组高分辨率 DNA 甲基化组谱分析。我们进行了全基因组表观遗传关联研究，通过进行全基因组条件逻辑回归，评估 IRs 的影响和蛋氨酸依赖性导向分析。我们在基因座和单个探针（CpG 二核苷酸）水平以及通过基因本体论（GO）的富集分析寻找表观基因组特征。EpiMet 项目在 ID#AAP-BMS_003_211 下注册。
EAS 揭示了与 IR 反应中几个生物学过程相关的增加甲基化特征的共享 GO 注释途径，包括血液循环、质膜边界细胞突起组织、细胞突起组织、多细胞生物体过程、发育过程和动物器官形态发生。对蛋氨酸依赖性表型的全基因组条件逻辑回归分析突出了几个与细胞周期和分裂以及对 IR 和紫外线的反应相关的表观基因组特征。
IR 产生了大量 CpG 探针的甲基化水平变化，这些探针具有共享的生物学途径，包括与细胞周期和分裂、对 IR 的反应、持续的血管生成、组织侵袭和转移相关的途径。这些结果提供了有关癌症细胞系对 IR 反应中表观基因组的共享适应机制的见解。未来的实验应集中在 IR、放射抗性表型的启动及其与蛋氨酸依赖性之间的相互作用上，因为这是癌症代谢适应的标志。
