非诺贝特与EZH2抑制剂联用提高电离辐射所致DNA损伤敏感性的效应与机制探索

肿瘤常伴有组蛋白甲基转移酶EZH2上调，电离辐射与EZH2抑制剂GSK126均可通过DNA损伤杀伤肿瘤，但临床上单独应用放疗与GSK126却未实现理想疗效。近期研究提示在抑制EZH2靶点H3K27me3基础上抑制H3K27乙酰化可明显提高EZH2抑制剂的效果。本课题组前期发现GSK126联合非诺贝特（FF）也存在对前者的增效表型，EZH2结合在DNA损伤相关基因ATM的转录调控区，GSK126可提高细胞对DNA损伤敏感性。因此，本课题拟将电离辐射联合EZH2抑制剂，辅以FF作为增敏剂，在小鼠模型以及不同细胞系中检测FF是否可进一步提高GSK126联合辐射所致DNA损伤的敏感性；该联合对DNA损伤及修复相关基因的表达影响及表观调控机制；回答FF是否可通过抑制糖酵解而间接抑制H3K27ac，进而实现对H3K27me3与H3K27ac的共抑制？这将有助于发现新型增敏剂及放化结合新方案。

DNA damage and repair is closely related to chemoradiotherapy of tumor. The expression of EZH2 which trimethylates H3K27 (H3K27me3) is generally up-regulated in cancers. However, after the EZH2 inhibitor GSK126 enrolled the phase II clinical trial, it was found that merely inhibiting H3K27me3 is still difficult to achieve the desired treatment effect. Recent studies revealed that concurrent inhibition of H3K27me and H3K27ac results in greater improvement in the effectiveness of single inhibitors. Our group previously found that EZH2 binds to the transcriptional regulatory region of DNA damage-related gene ATM. GSK126 could increase the sensitivity of cells upon DNA damage, and combined with the metabolic regulation drug fenofibrate (FF) could enhance inhibition of tumor. Hence， this study intends to explore whether FF can further improve the sensitivity of GSK126 under radiation-induced DNA damage condition in mouse models and different tumor cell lines by combining ionizing radiation with EZH2 inhibitors and applying FF as radiation sensitizer. We would like to further explore whether FF inhibit H3K27ac by inhibiting glycolysis， so as to achieve the co-inhibitory effect of GSK126 combined with FF on H3K27me3 and H3K27ac. This will provide new strategies for novel sensitizers of DNA damage and the combination of chemotherapy and irradiation therapy.