Functional requirement of a wild-type allele for mutant IDH1 to suppress anchorage-independent growth through redox homeostasis.

Published

Journal Article

Mutations of isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, arguably preceding all known genetic alterations during tumor development. IDH1 mutations nearly invariably target the enzymatic active site Arg132, giving rise to the predominant IDH1R132H. Cells harboring IDH1 R132H -heterozygous mutation produce 2-hydroxyglutarate (2-HG), which results in histone and DNA hypermethylation. Although exogenous IDH1 R132H transduction has been shown to promote anchorage-independent growth, the biological role of IDH1R132H in glioma remains debatable. In this study, we demonstrate that heterozygous IDH1 R132H suppresses but hemizygous IDH1 R132H promotes anchorage-independent growth. Whereas genetic deletion of the wild-type allele in IDH1 R132H -heterozygous cells resulted in a pronounced increase in neurosphere genesis, restoration of IDH1 expression in IDH1 R132H -hemizygous cells led to the contrary. Conversely, anchorage-independent growth was antagonistic to the mutant IDH1 function by inhibiting gene expression and 2-HG production. Furthermore, we identified that in contrast to IDH1 R132H -hemizygous neurosphere, IDH1 R132H -heterozygous cells maintained a low level of reducing power to suppress neurosphere genesis, which could be bypassed, however, by the addition of reducing agent. Taken together, these results underscore the functional importance of IDH1 mutation heterozygosity in glioma biology and indicate functional loss of mutant IDH1 as an escape mechanism underlying glioma progression and the pathway of redox homeostasis as potential therapeutic targets.

Full Text

Duke Authors

Cited Authors

  • Tiburcio, PDB; Xiao, B; Berg, S; Asper, S; Lyne, S; Zhang, Y; Zhu, X; Yan, H; Huang, LE

Published Date

  • February 2018

Published In

Volume / Issue

  • 135 / 2

Start / End Page

  • 285 - 298

PubMed ID

  • 29288440

Pubmed Central ID

  • 29288440

Electronic International Standard Serial Number (EISSN)

  • 1432-0533

Digital Object Identifier (DOI)

  • 10.1007/s00401-017-1800-0

Language

  • eng

Conference Location

  • Germany