RNA Methylation in Metabolically Disrupted Pediatric Cancers
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. 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 - June 2020
The present study addresses an important 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 will develop an initial blueprint of RNA methylation changes that may be key contributors to the tumorigenic process. In the first year of this award, we developed critical resources to enable our studies. In an effort to understand more broadly the effect of cancer-causing genetic mutations of metabolic genes in RNA regulation, we created and refined new cell models of SDHB deficiency alone or in combination with disruption of other regulators of RNA methylation. By examining these new models, we found that the nature of the metabolite and the cell type both impacts the outcome of RNA methylation, revealing a high degree of specificity of this regulation. These various cells and tumor models will be used in the second year of this award to evaluate the genes that are affected by metabolite accumulation and which may contribute to the oncogenic properties of SDHB deficiency. We will begin to test which of these changes can be potentially reversible by restoring the metabolic status of these cells. These are concrete steps toward exploiting these cancer vulnerabilities for future therapeutic purposes.