m6A甲基化通过KMT5A调控胶质母细胞瘤替莫唑胺耐药的机制研究

替莫唑胺（TMZ）耐药是胶质母细胞瘤（GBM）术后病情恶化及治疗失败的关键原因，因此探究TMZ耐药的调控新机制是亟待解决的问题。申请人在已发表工作证实m6A和其甲基转移酶METTL3调控GBM的发生发展。申请人最近进一步研究又发现在TMZ耐药的GBM中m6A修饰水平异常增高，敲降METTL3下调m6A可以促进GBM对TMZ的治疗敏感性，m6A修饰通过无义介导mRNA降解（NMD）调控KMT5A的表达。因此提出科学假说：胶质母细胞瘤中m6A异常增高有助于躲避NMD纠错机制，促进KMT5A的mRNA水平上调，导致GBM发生表观遗传重编程产生TMZ耐药。本项目拟阐明m6A甲基化通过NMD调控KMT5A表达的分子机理、揭示m6A通过KMT5A在胶质母细胞瘤TMZ耐药中的作用和分子机制、明确TMZ联合KMT5A抑制剂UNC0379对耐药GBM的治疗作用。本项目对改善TMZ治疗效果有着积极的临床意义。

Temozolomide (TMZ) resistance is the key cause of postoperative deterioration and treatment failure of glioblastoma (GBM). Therefore, the new regulatory mechanism of TMZ resistance needed to be studied urgently. The applicant has demonstrated in published work that m6A and its m6A methyltransferase METTL3 regulate the process of GBM. Recent applicant's research shows that abnormally elevated m6A modification were observed in TMZ resistant GBM, m6A modification regulates the expression of KMT5A through NMD, and thus affects the TMZ resistance of GBM. Therefore, we propose a scientific hypothesis: abnormally elevated m6A modification in TMZ resistance GBM promotes the expression of KMT5A by modulates NMD pathway, leading to epigenetic reprogramming of GBM and TMZ drug resistance. This project aims to clarify the molecular mechanism of m6A regulate the expression of KMT5A through NMD, reveal the role and mechanism of m6A in TMZ resistance GBM through regulate the expression of KMT5A, and verify the therapeutic effect of TMZ combined with KMT5A inhibitor UNC0379 on drug-resistant GBM. This study has positive clinical significance in improving the efficacy and prognosis of drug-resistant GBM patients.