Isocitrate Dehydrogenase 3 and One-Carbon Metabolism: Defining a Novel Role for Isocitrate Dehydrogenase 3 in Glioblastoma

May, Jasmine Louise

doi:https://doi.org/10.21985/n2-y5pv-dh68

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Isocitrate Dehydrogenase 3 and One-Carbon Metabolism: Defining a Novel Role for Isocitrate Dehydrogenase 3 in Glioblastoma

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Glioblastoma (GBM) is a highly malignant brain tumor that accounts for the most commonly diagnosed type of primary brain tumors in adults. It has a poor prognosis of only 15 months from the time of diagnosis. The gold standard therapy regimen consists of radiotherapy and the chemotherapeutic temozolomide. Both of these therapies can have major side effects and no major strides have been made to improve the therapeutic options or outcomes. Many researchers have been investigating GBM to discover druggable targets that might have fewer side effects and improve disease prognosis. Of late many researchers have been investigating a group of enzymes called isocitrate dehydrogenase (IDH) enzymes. They are a key group of enzymes important for the conversion of isocitrate (ICT) to α-ketoglutarate (α-KG). IDH1 carries out this conversion in the cytosol supplying α-KG. α-KG is important for fatty acid synthesis and to act as a co-factor for other enzymes that regulate histone methylation and protein degradation. IDH2 and IDH3 carry out the reaction as part of the tricarboxylic acid (TCA) cycle. Therefore, IDH2 and IDH3 are important for energy production in the mitochondria. IDH1 and IDH2 have frequently been found to be mutated in the setting of GBM, in particular in secondary GBM, GBM that develops from low grade gliomas, while wild type IDH1 is more commonly found in primary GBM, GBM that arises de novo. Recently our lab determined that wild type IDH1 promotes primary GBM growth and receptor tyrosine kinase inhibitor resistance. While IDH1 and IDH2 has been the focus in GBM research, very little has been discovered with regards to IDH3. Interestingly IDH3 is rarely found mutated in the setting of GBM and the reason for this has remained unclear. Unique to IDH3 compared to its family members is that IDH3 is a heterotetramer, composed of four subunits, two α, one β, and one γ subunit. Its main function is as part of the TCA cycle to convert ICT to α-KG, like IDH2, but some researchers have hinted at alternative functions, including one that may involve a nuclear role for IDH3, in particular for the α subunit (IDH3α). My research focuses on confirming nuclear localization of IDH3α and elucidating the role that it plays at the nucleus. Through a non-biased approach we have identified a novel interactor, cytosolic serine hydroxymethyltransferase (cSHMT), with IDH3α. We have determined that IDH3α regulates cSHMT activity, promoting thymidylate synthesis at the nuclear lamina. In the absence of IDH3α expression we observed decreased proliferation, increased sensitivity to the anti-folate chemotherapeutic methotrexate (MTX), and increased flux of folate metabolites through the methionine pathway, ultimately leading to an overall increase in DNA methylation. These effects result in decreased tumor growth and thus increased survival in vivo and the epigenetic changes caused a deregulation of pathways like the cAMP mediated signaling and regulation of epithelial-to-mesenchymal transition pathways. Thus, we have discovered a novel role for IDH3α in GBM pathogenesis and in general cellular physiology. Based off our research IDH3α appears to be a novel metabolic target for future therapies that may improve GBM patient outcomes.

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