Evaluating the role of EZH2-interacting protein (EZHIP) in pediatric posterior fossa ependymoma metabolism

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ABSTRACT Pediatric ependymomas are the third-most common malignancy of the central nervous system. While they arise in different places of the neuraxis, these tumors are most commonly seen in the posterior fossa region of the brain. Posterior fossa ependymomas have been stratified into two groups (Group A and Group B) based on DNA methylation, transcriptional, and clinical profiling. Of these two groups, Group A (also referred to as PFA) is more invasive and carries a worse prognosis. These tumors are resistant to chemotherapy and arise in sensitive locations that may render them inoperable. PFAs are unusual as more than 80% of these tumors do not bear recurrent genetic mutations. Interestingly, these tumors are defined by global loss of transcriptionally- repressive histone modification H3K27me3 and global gain of transcriptionally-activating histone modification H3K27ac. Alterations in DNA methylation and global H3K27me3 reduction indicate that PFAs are epigenetically driven. EZH2-inhibitory protein (EZHIP) is a novel protein that is expressed highly in PFAs and drives global reduction of H3K27me3 by inhibiting the activity of histone methyltransferase EZH2. It remains unknown how EZHIP expression and H3K27me3 loss drives tumorigenicity in PFA ependymomas. Strikingly, RNA-sequencing analysis of PFAs show upregulation of the pyruvate dehydrogenase complex, a key metabolic complex that links glycolysis and the TCA-cycle. Subsequent metabolomic and RNA analysis show that glycolytic and TCA-cycle metabolism are also enhanced in these tumors. Based on these preliminary data, I hypothesize that EZHIP expression upregulate PFA metabolism by epigenetically activating the pyruvate dehydrogenase complex. To test this hypothesis, I will characterize the epigenetic and metabolic effect of exogenous EZHIP expression in neuronal stem cells and EZHIP deletion in patient-derived PFA cell lines. To define the role of the PDC on tumor pathogenesis, I will target PDC expression via RNA-interference and pharmacological inhibition and determine the effect on PFA growth in vivo and in vitro. These experiments will provide novel mechanistic insights into PFA growth and will provide solid scientific data that may inform future therapeutic strategies.