Glioma-Derived Mutations in <i>IDH1</i> Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α

TLDR

Heterozygous mutations in the IDH1 gene occur in certain human brain tumors, but their mechanistic role in tumor development is unknown. Forced expression of mutant IDH1 in cultured cells reduces α‑ketoglutarate production and increases HIF‑1α levels, a transcription factor whose stability is regulated by α‑KG. Tumor‑derived IDH1 mutations diminish substrate affinity and dominantly inhibit wild‑type activity through inactive heterodimers, elevate HIF‑1α (reversible by an α‑KG derivative), and are associated with higher HIF‑1α in gliomas, indicating that loss of IDH1 function promotes tumorigenesis partly via HIF‑1 activation.

Abstract

Heterozygous mutations in the gene encoding isocitrate dehydrogenase-1 ( IDH1 ) occur in certain human brain tumors, but their mechanistic role in tumor development is unknown. We have shown that tumor-derived IDH1 mutations impair the enzyme's affinity for its substrate and dominantly inhibit wild-type IDH1 activity through the formation of catalytically inactive heterodimers. Forced expression of mutant IDH1 in cultured cells reduces formation of the enzyme product, α-ketoglutarate (α-KG), and increases the levels of hypoxia-inducible factor subunit HIF-1α, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by α-KG. The rise in HIF-1α levels was reversible by an α-KG derivative. HIF-1α levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Thus, IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF-1 pathway.