IDH3α regulates one-carbon metabolism in glioblastoma.

Published online

Journal Article

Mutation or transcriptional up-regulation of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) promotes cancer progression through metabolic reprogramming and epigenetic deregulation of gene expression. Here, we demonstrate that IDH3α, a subunit of the IDH3 heterotetramer, is elevated in glioblastoma (GBM) patient samples compared to normal brain tissue and promotes GBM progression in orthotopic glioma mouse models. IDH3α loss of function reduces tricarboxylic acid (TCA) cycle turnover and inhibits oxidative phosphorylation. In addition to its impact on mitochondrial energy metabolism, IDH3α binds to cytosolic serine hydroxymethyltransferase (cSHMT). This interaction enhances nucleotide availability during DNA replication, while the absence of IDH3α promotes methionine cycle activity, S-adenosyl methionine generation, and DNA methylation. Thus, the regulation of one-carbon metabolism via an IDH3α-cSHMT signaling axis represents a novel mechanism of metabolic adaptation in GBM.

Full Text

Duke Authors

Cited Authors

  • May, JL; Kouri, FM; Hurley, LA; Liu, J; Tommasini-Ghelfi, S; Ji, Y; Gao, P; Calvert, AE; Lee, A; Chandel, NS; Davuluri, RV; Horbinski, CM; Locasale, JW; Stegh, AH

Published Date

  • January 2019

Published In

Volume / Issue

  • 5 / 1

Start / End Page

  • eaat0456 -

PubMed ID

  • 30613765

Pubmed Central ID

  • 30613765

Electronic International Standard Serial Number (EISSN)

  • 2375-2548

Digital Object Identifier (DOI)

  • 10.1126/sciadv.aat0456

Language

  • eng

Conference Location

  • United States