Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α

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.

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

“…L-2HG acts to stabilize hypoxia-inducible factors by inhibiting the αKG-dependent prolyl hydroxylases that target HIF for degradation 11,13 . Whether HIF-1α stabilization is a qualitatively or quantitatively unique property of L-2HG compared to D-2HG remains controversial 13,47,48 . We have identified acidosis as previously unappreciated physiologic stimulus that enhances conversion of αKG to L-2HG, resulting in robust stabilization of HIF-1α in normoxia.…”

The immortalizing and transforming ability of two common human papillomavirus 16 E6 variants with different prevalences in cervical cancer

“…Indeed, the Warburg effect has been reported to be essential for immortalization and transformation, as it renders cells resistant to oxidative stress and adaptive to hypoxia (Kondoh, 2008). Interestingly, disruption of an extra-mitochondrial process, characterized by reduced IDH1 activity and caused by tumor-associated mutations, has recently been reported for glioblastoma multiforme, a malignant brain tumor (Zhao et al, 2009). Reduced IDH1 activity leads to low levels of alpha-ketoglutarate in the cytosol and activation of hypoxia-induced factor, which promotes the transcription of genes functioning in energy metabolism, growth and differentiation (Pollard and Ratcliffe, 2009).…”

Genetic alterations of IDH1 and Vegf in brain tumors

“…When IDH1 gene is mutated, the α‐KG is not generated, and the α‐KG‐dependent dioxygenases are inactive. These dioxygenases are thought to be involved in epigenetic control, suggesting that mutations in  IDH1  can affect a large number of genes (Watanabe, Nobusawa, Kleihues, & Ohgaki, 2009; Zhao et al., 2009). IDH1 mutations are likely to be a direct cancer driver in early stage of gliomagenesis promoting extensive alteration of the epigenetic pattern (Turcan et al., 2012; Watanabe et al., 2009).…”