The RNA‐binding protein Imp2 regulates oxidative phosporylation that is key to glioblastoma cancer stem cell maintenance

Insulin‐like growth factor 2 mRNA binding protein 2 (Imp2, IGF2BP2) is expressed during embryonic brain development and associated with several types of cancer. We have found that 75% cases of glioblastoma multiforme (GBM), the most malignant type of glioma, express Imp2, whereas low grade gliomas and normal adult brain do not. Interestingly expression of Imp2 was particularly elevated in GBM cancer stem cells (CSC). Immunoprecipitation of Imp2‐containing ribonucleoprotein complexes from CSC spheroids revealed that mRNAs as well as proteins bound by Imp2, including the respiratory complex I protein NDUFS3, play a role in mitochondrial energy production. Imp2 depletion severely reduced GBM CSC ability to form spheroids and to initiate tumor growth. Proliferation, ATP content and oxygen consumption rate were also diminished in GBM CSC depleted of Imp2 due to an Imp2 depletion‐dependent defect in complex I assembly and activity. Inhibition of oxidative phosphorylation (OxPhos) in GBM CSC with the selective respiratory complex I inhibitor rotenone, mimicked the effect of Imp2 silencing. By contrast, GBM CSC‐derived non tumorigenic cells were not affected by rotenone, but were sensitive to the anaerobic glycolysis inhibitor oxamic acid. Our observations provide evidence for an unsuspected function of Imp2 in the control of OxPhos and demonstrate its key role in GBM CSC maintenance.