RNA-binding protein hur regulates both mutant and wild-type IDH1 in IDH1-mutated cancer

Mahsa Zarei, Shruti Lal, Ali Vaziri-Gohar, Kevin O'Hayer, Venugopal Gunda, Pankaj K. Singh, Jonathan R. Brody, Jordan M. Winter

Research output: Contribution to journalArticle

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Abstract

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic enzyme in human malignancy. A heterozygous genetic alteration, arginine 132, promotes the conversion of a-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.

Original languageEnglish (US)
Pages (from-to)508-520
Number of pages13
JournalMolecular Cancer Research
Volume17
Issue number2
DOIs
StatePublished - Feb 2019

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Isocitrate Dehydrogenase
RNA-Binding Proteins
Neoplasms
Mutation
Clustered Regularly Interspaced Short Palindromic Repeats
Genetic Suppression
Pentose Phosphate Pathway
Messenger RNA
Ribonucleoproteins
Metabolomics

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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RNA-binding protein hur regulates both mutant and wild-type IDH1 in IDH1-mutated cancer. / Zarei, Mahsa; Lal, Shruti; Vaziri-Gohar, Ali; O'Hayer, Kevin; Gunda, Venugopal; Singh, Pankaj K.; Brody, Jonathan R.; Winter, Jordan M.

In: Molecular Cancer Research, Vol. 17, No. 2, 02.2019, p. 508-520.

Research output: Contribution to journalArticle

Zarei, M, Lal, S, Vaziri-Gohar, A, O'Hayer, K, Gunda, V, Singh, PK, Brody, JR & Winter, JM 2019, 'RNA-binding protein hur regulates both mutant and wild-type IDH1 in IDH1-mutated cancer', Molecular Cancer Research, vol. 17, no. 2, pp. 508-520. https://doi.org/10.1158/1541-7786.MCR-18-0557
Zarei, Mahsa ; Lal, Shruti ; Vaziri-Gohar, Ali ; O'Hayer, Kevin ; Gunda, Venugopal ; Singh, Pankaj K. ; Brody, Jonathan R. ; Winter, Jordan M. / RNA-binding protein hur regulates both mutant and wild-type IDH1 in IDH1-mutated cancer. In: Molecular Cancer Research. 2019 ; Vol. 17, No. 2. pp. 508-520.
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abstract = "Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic enzyme in human malignancy. A heterozygous genetic alteration, arginine 132, promotes the conversion of a-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.",
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AU - Zarei, Mahsa

AU - Lal, Shruti

AU - Vaziri-Gohar, Ali

AU - O'Hayer, Kevin

AU - Gunda, Venugopal

AU - Singh, Pankaj K.

AU - Brody, Jonathan R.

AU - Winter, Jordan M.

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