RNA Methylation in Metabolically Disrupted Pediatric Cancers
Background: Epigenetic changes, including methylation, are reversible chemical modifications that can affect gene expression. DNA, histones (the proteins that package the DNA) and RNA are subject to such modifications. Aberrant DNA and histone methylation have been clearly linked to cancer, however, the impact of RNA methylation in cancers is poorly understood.
Project Goal: In the present study, we propose that the deregulation of RNA methylation is pervasive in cancers with mutations in energy metabolism genes. To test this hypothesis, we propose to study a rare neuroendocrine cancer, paraganglioma, that arises as the result of an inherited mutation of a metabolic gene known as SDHB. Over 70% of children with metastatic paragangliomas have an inherited SDHB mutation and currently, treatment options are limited. Studying the effects of SDHB mutation on RNA methylation may reveal novel markers of metastatic risk in these tumors. Moreover, the findings of our research may be relevant to other cancers, especially those affecting metabolic genes. Importantly, the reversible nature of RNA methylation may shed light on the development of novel approaches to reverse the oncogenic effects of these epigenetic aberrations.
Project Update 2021: The present study focused on a gap in our knowledge of rare cancers that carry mutations in metabolic genes, including pediatric paragangliomas with SDHB mutation: the role of RNA methylation, a potentially reversible process. We generated a global map of RNA methylation changes in cells deficient in SDHB, and in two components of the RNA methylation system. Although we have not found a marked global change in RNA methylation in SDHB mutation, we were able to identify some candidate genes that may be impacted by RNA methylation that will need further validation. These genes may be contributors to the process of transformation of these tumors and further study will allow us to exploit these cancer vulnerabilities for therapeutic development.
