PCIF1介导的 LAMTOR1 m6Am甲基化修饰在胶质瘤生长中的作用及机制研究

RNA甲基化在基因表达调控中发挥重要作用，PCIF1是生成N6,2'-O-二甲基腺苷（m6Am）的甲基转移酶。我们前期研究表明下调PCIF1促进胶质母细胞瘤（GBM）生长，但其作用机制尚不清楚。结合公开的m6Am测序数据、我们在GBM样本中的质谱定量分析和后续验证，我们发现在GBM组织中高表达的LAMTOR1存在m6Am甲基化修饰，它的蛋白水平受PCIF1的酶活性负性调节。LAMTOR1据报道促进mTOR激活。因此，PCIF1介导的m6Am修饰减少导致LAMTOR1表达增加，后者通过活化mTOR信号通路促进胶质瘤生长。本项目拟以胶质瘤标本、细胞系和动物模型为研究对象，分析PCIF1与胶质瘤病理分级分型和临床预后的关系，阐明PCIF1介导的LAMTOR1 m6Am 甲基化影响胶质瘤生长和mTOR信号转导的分子机制。预期研究结果将为靶向mTOR上游驱动因子的抗胶质瘤药物研发提供候选靶点。

RNA methylation plays an important role in gene expression regulation, PCIF1 is an RNA methyltransferase that produces N6,2'-O-dimethyladenosine (m6Am). Our previous studies have shown that down-regulating PCIF1 promotes glioblastoma (GBM) growth, but its mechanism of action remains unclear. Combining published m6Am sequencing data, our quantitative analysis in GBM samples by mass spectrometry, and subsequent validation, we found that LAMTOR1 existed m6Am modification and was highly expressed in GBM tissues, and its protein level was negatively regulated by the enzyme activity of PCIF. LAMTOR1 is reported to promote mTOR activation. Therefore, the reduction of PCIF1-mediated m6Am modification leads to increased expression of LAMTOR1, which in turn promotes the growth of gliomas by activating the mTOR signaling pathway. This project aims to use glioma specimens, cell lines and animal models as the research subjects to analyze the relationship between PCIF1 and glioma pathological classification and clinical prognosis, and to elucidate the molecular mechanism by which PCIF1-mediated LAMTOR1 m6Am methylation affects glioma growth and mTOR signal transduction. We expect to provide candidate targets for the development of anti-glioma drugs that target the upstream drivers of mTOR.