Elucidating the regulation of RNA methylation by mTOR signaling in cancer

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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.