Epigenetic deregulations are those that lead to change in gene levels without altering the genetic code. Epigenetic remodeling is an integral part of cancer initiation, maintenance and progression. DNA methylation is the most studied epigenetic change. However, recent evidence suggests that RNA methylation is as important as DNA methylation to human physiology and pathology, including cancer. RNA methylation is tightly controlled by the abundance and activity of proteins that promote it (RNA methyltransferase) and those that terminate it (RNA demethylases). We discovered that a ubiquitous cancer promoting gene, MYC, is a critical regulator of RNA methylation. Our data suggest that MYC induce...

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Epigenetic deregulations are those that lead to change in gene levels without altering the genetic code. Epigenetic remodeling is an integral part of cancer initiation, maintenance and progression. DNA methylation is the most studied epigenetic change. However, recent evidence suggests that RNA methylation is as important as DNA methylation to human physiology and pathology, including cancer. RNA methylation is tightly controlled by the abundance and activity of proteins that promote it (RNA methyltransferase) and those that terminate it (RNA demethylases). We discovered that a ubiquitous cancer promoting gene, MYC, is a critical regulator of RNA methylation. Our data suggest that MYC induces the activity of RNA demethylases and thus lowers the global level of RNA methylation in the cell. Our overall hypothesis is that MYC is an important regulator of RNA methylation in cancer, and that this interplay is an important part of the pro-cancer activities of MYC. To validate this hypothesis, we will use B cell lymphoma as a cancer model to characterize the correlation between MYC expression and methylRNA levels in primary tumor biopsies, and to examine the contribution of mitochondrial metabolism in linking MYC to RNA demethylases. In addition, using mouse models and genetically modified lymphoma cell lines we will determine how much of the pro-cancer role of MYC stems from its ability to influence methylation. Considering the extensive contribution of MYC to several tumor types (brain, breast, leukemia, lymphoma, etc.), this project will broadly expand our understanding of cancer biology. From a translational viewpoint, the completion of these studies may lead to the development of RNA demethylase inhibitors as agents that suppress MYC-driven cancers. Lastly, in this project we will define a MYC-driven/RNA methylation-dependent gene signature, which may uncover additional MYC-related cancer dependencies and reveal novel therapeutic targets.

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