EBV膜蛋白LMP1调控H3K4me3/H3K27me3表观重编程导致鼻咽癌耐药的机制研究

肿瘤细胞耐药是晚期鼻咽癌治疗失败的主要原因，而组蛋白甲基化修饰紊乱是导致肿瘤细胞耐药的关键机制。我们前期研究发现LMP1能够调控基因启动子上H3K4me3/H3K27me3甲基化修饰，并观察到高表达LMP1可导致鼻咽癌细胞对顺铂和5-氟尿嘧啶耐药，RNA-seq进一步分析发现肿瘤耐药基因在LMP1阳性细胞中显著富集，提示组蛋白甲基化修饰紊乱可能是LMP1导致鼻咽癌耐药的关键因素。因此，本项目拟通过ChIP-Seq测序建立LMP1调控H3K4me3/H3K27me3的甲基化修饰谱，结合前期RNA-seq表达谱分析筛选出LMP1调控H3K4me3/H3K27me3导致鼻咽癌耐药的关键靶基因，进一步探索该基因导致鼻咽癌耐药的分子机制，并在动物模型和临床样本中验证该基因对鼻咽癌耐药的影响。本研究的顺利完成将为逆转鼻咽癌耐药提供新的理论依据和潜在治疗靶点。

Chemoresistance of tumor cells is the main reason for the failure of advanced nasopharyngeal carcinoma treatment. The disorder of histone methylation modification in tumor cells is the key mechanism leading to chemoresistance. Our previous study found that LMP1 was able to regulate H3K4me3/H3K27me3 on the gene promoter and observed that high expression of LMP1 could induce resistance to cisplatin and 5-fluorouracil of nasopharyngeal carcinoma cells.Further analysis of the RNA-seq data, we found that tumor resistance related genes were significantly enriched in LMP1-positive cells, suggesting that histone methylation deregulation may be crucial in LMP1-induced chemoresistance. Therefore, this project aims to establish the pattern of LMP1-regulated H3K4me3/H3K27me3 by ChIP-Seq sequencing, and screen the key target genes regulated by LMP1-induced H3K4me3/H3K27me3 and combined analysis the RNA-seq data. Next, we would explore the molecular mechanism of LMP1 conferred drug resistance and to verify the effect of target genes in animal model and clinical sample. Our study will provide new potential therapeutic targets to bypass the chemoresistance of nasopharyngeal carcinoma.