Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic
enzyme in human
malignancy. A heterozygous genetic alteration,
arginine 132, promotes the conversion of α-ketoglutarate to
D-2-hydroxyglutarate (2-HG). Although pharmacologic inhibitors of mutant IDH1 are promising, resistance mechanisms to targeted
therapy are not understood. Additionally, the role of wild-type IDH1 (WT.IDH1) in
cancer requires further study. Recently, it was observed that the regulatory
RNA-binding protein, HuR (ELAVL1), protects nutrient-deprived
cancer cells without IDH1 mutations, by stabilizing WT.IDH1 transcripts. In the present study, a similar regulatory effect on both mutant (Mut.IDH1) and WT.IDH1 transcripts in heterozygous IDH1-mutant
tumors is observed. In
ribonucleoprotein immunoprecipitation assays of IDH1-mutant cell lines, wild-type and mutant IDH1 mRNAs each bound to HuR. Both
isoforms were profoundly downregulated at the
mRNA and
protein levels after genetic suppression of HuR (siRNAs or CRISPR deletion) in HT1080 (R132C IDH1 mutation) and BT054 cells (R132H). Proliferation and invasion were adversely affected after HuR suppression and metabolomic studies revealed a reduction in Pentose Phosphate Pathway metabolites,
nucleotide precursors, and 2-HG levels. HuR-deficient cells were especially sensitive to stress, including low
glucose conditions or a mutant IDH1 inhibitor (AGI-5198). IDH1-mutant
cancer cells were rescued by WT.IDH1 overexpression to a greater extent than Mut.IDH1 overexpression under these conditions. This study reveals the importance of HuR's regulation of both mutant and wild-type IDH1 in
tumors harboring a heterozygous IDH1 mutation with implications for
therapy. IMPLICATIONS: This study highlights the HuR-IDH1 (mutant and wild-type IDH1) regulatory axis as a critical, actionable therapeutic target in IDH1-mutated
cancer, and incomplete blockade of the entire HuR-IDH1 survival axis would likely diminish the efficacy of drugs that selectively target only the mutant
isoenzyme.