Elucidating the regulation of RNA methylation by mTOR signaling in cancer

项目摘要/摘要 在过去的十年中，我们对RNA化学修饰的知识，如N6-腺苷甲基化(M6A) 由于转录组范围测序技术的发展和几个 检测RNA修饰的方法。新的证据表明，m6A修饰在mRNAs上的改变 编码癌基因和抑癌基因与癌症的发生和发展有关，包括 白血病、胶质瘤、乳腺癌和肺癌。这些RNA修饰是由几个RNA结合处理的 蛋白质，如RNA甲基转移酶和去甲基酶。这些酶的表达和活性 在肿瘤发生过程中可能受到上游信号通路的调节，然而，我们的理解是 信号转导途径如何控制这些酶以及随后的RNA修饰仍然是 很初级的。通过对mTOR信号通路的磷酸蛋白质组学和转录组学分析，我已经 确定了mTOR信号和调节m6A RNA甲基化的酶之间的联系。我的工作 初步数据支持的假说是mTOR途径，通过调节表达和 M6A甲基转移酶复合体的活性控制着mRNA的代谢。更重要的是，我的数据表明 这种mTOR-m6A信号调节参与一碳代谢的酶的表达，a 癌细胞的高增殖率和生存所需的代谢途径。拟议中的实验 策略将揭示mTOR信号如何通过以下途径控制癌基因和肿瘤抑制基因的表达 RNA甲基化，及其与癌症中一碳代谢的联系。成功完成这项工作 该提案将为新的癌症生物标记物和治疗靶向的表征提供理论基础 致癌信号通路下游的RNA甲基化过程。

PROJECT SUMMARY/ABSTRACT Over the past decade, our knowledge of RNA chemical modifications such as N6-adenosine methylation (m6A) on mRNAs has increased due to the development of transcriptome-wide sequencing technologies and several assays to detect RNA modifications. Emerging evidence shows that alteration of m6A modification on mRNAs encoding oncogenes and tumor suppressors is linked to cancer development and progression including leukemia, glioma, breast and lung cancers. These RNA modifications are processed by several RNA binding proteins such as RNA methyl transferases and demethylases. The expression and activities of these enzymes are likely to be modulated by upstream signaling pathways during tumorigenesis, however, our understanding of how signal transduction pathway controls these enzymes and the consequent RNA modifications is still rudimentary. Through phosphoproteomic and transcriptomic analysis of the mTOR signaling pathway, I have identified links between the mTOR signaling and enzymes that regulate m6A RNA methylation. My working hypothesis, which is supported by preliminary data, is that mTOR pathway, by regulating the expression and activities of m6A methyl transferase complex, controls mRNA metabolism. More importantly, my data suggest that this mTOR-m6A signaling regulates the expression of enzymes involved in one-carbon metabolism, a metabolic pathway required for high proliferation rate and survival of cancer cells. The proposed experimental strategies will reveal how mTOR signaling controls expression of oncogenes and tumor suppressors through RNA methylation, and its connection to one-carbon metabolism in cancer. Successful completion of this proposal will provide a rationale for the characterization of new cancer biomarkers and therapeutics targeting RNA methylation process downstream of oncogenic signaling pathways.