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

Acta Neuropathologica volume 135, pages 285–298 (2018)Cite this article

Abstract

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 IDH1R132H-heterozygous mutation produce 2-hydroxyglutarate (2-HG), which results in histone and DNA hypermethylation. Although exogenous IDH1R132H 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 IDH1R132H suppresses but hemizygous IDH1R132H promotes anchorage-independent growth. Whereas genetic deletion of the wild-type allele in IDH1R132H-heterozygous cells resulted in a pronounced increase in neurosphere genesis, restoration of IDH1 expression in IDH1R132H-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 IDH1R132H-hemizygous neurosphere, IDH1R132H-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.

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Acknowledgements

We wish to thank Kristin Kraus for editorial assistance and Rodney Stewart for providing mCherry cDNA. We acknowledge the Metabolomics Core, the Fluorescence Microscope Core, and the Flow Cytometry Facility at the University of Utah for providing services. This work was supported in part by a National Institutes of Health Grant (CA084563) from the National Cancer Institute, the Department of Neurosurgery at the University of Utah, funds in conjunction with Grant P30CA042014 awarded to Huntsman Cancer Institute and to the Nuclear Control Program at Huntsman Cancer Institute, and an award from the Foreign Science and Technology Cooperation Plan of Jiangxi Province (20151BDH80009).

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  1. Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, 175 North Medical Drive East, Salt Lake City, UT, 84132, USA

    Patricia D. B. Tiburcio, Bing Xiao, Shauna Berg, Sydney Asper, Sean Lyne & L. Eric Huang

  2. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA

    Patricia D. B. Tiburcio & L. Eric Huang

  3. Department of Neurosurgery, Nanchang University Second Affiliated Hospital, Nanchang, Jiangxi, People’s Republic of China

    Bing Xiao, Yan Zhang & Xingen Zhu

  4. Department of Pathology, Duke University Medical Center, Durham, NC, USA

    Hai Yan

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  1. Patricia D. B. Tiburcio
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Tiburcio, P.D.B., Xiao, B., Berg, S. et al. Functional requirement of a wild-type allele for mutant IDH1 to suppress anchorage-independent growth through redox homeostasis. Acta Neuropathol 135, 285–298 (2018). https://doi.org/10.1007/s00401-017-1800-0

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Keywords

  • Anchorage-independent growth
  • Glioma progression
  • Heterozygosity
  • Isocitrate dehydrogenase 1
  • Neurosphere
  • Redox homeostasis