Cited by 210Glioma Diagnosis and TreatmentCancer, Hypoxia, and MetabolismAcute Myeloid Leukemia Research

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Lactate dehydrogenase A silencing in IDH mutant gliomas

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Chesnelong, Charles, Chaumeil, Myriam M., Blough, Michael D., Al-Najjar, Mohammad, Stechishin, Owen D., Chan, Jennifer A., Pieper, Russell O., Ronen, Sabrina M., Weiss, Samuel, Luchman, H. Artee, Cairncross, J. Gregory·2014·Neuro-Oncology

DOI 10.1093/neuonc/not243PMC PMC3984548

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Abstract

BACKGROUND: Mutations of the isocitrate dehydrogenase 1 and 2 gene (IDH1/2) were initially thought to enhance cancer cell survival and proliferation by promoting the Warburg effect. However, recent experimental data have shown that production of 2-hydroxyglutarate by IDH mutant cells promotes hypoxia-inducible factor (HIF)1α degradation and, by doing so, may have unexpected metabolic effects. METHODS: We used human glioma tissues and derived brain tumor stem cells (BTSCs) to study the expression of HIF1α target genes in IDH mutant ((mt)) and IDH wild-type ((wt)) tumors. Focusing thereafter on the major glycolytic enzyme, lactate dehydrogenase A (LDHA), we used standard molecular methods and pyrosequencing-based DNA methylation analysis to identify mechanisms by which LDHA expression was regulated in human gliomas. RESULTS: We found that HIF1α-responsive genes, including many essential for glycolysis (SLC2A1, PDK1, LDHA, SLC16A3), were underexpressed in IDH(mt) gliomas and/or derived BTSCs. We then demonstrated that LDHA was silenced in IDH(mt) derived BTSCs, including those that did not retain the mutant IDH1 allele (mIDH(wt)), matched BTSC xenografts, and parental glioma tissues. Silencing of LDHA was associated with increased methylation of the LDHA promoter, as was ectopic expression of mutant IDH1 in immortalized human astrocytes. Furthermore, in a search of The Cancer Genome Atlas, we found low expression and high methylation of LDHA in IDH(mt) glioblastomas. CONCLUSION: To our knowledge, this is the first demonstration of downregulation of LDHA in cancer. Although unexpected findings, silencing of LDHA and downregulation of several other glycolysis essential genes raise the intriguing possibility that IDH(mt) gliomas have limited glycolytic capacity, which may contribute to their slow growth and better prognosis.

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Authors: Chesnelong, C., Chaumeil, M. M., Blough, M. D., Al-Najjar, M., Stechishin, O. D., Chan, J. A., Pieper, R. O., Ronen, S. M., Weiss, S., Luchman, H. A., & Cairncross, J. G.
Affiliations: Foothills Medical Centre (CA)
Corresponding author: Cairncross, J. Gregory
ORCID: Chaumeil, Myriam M.
Blough, Michael D.
Chan, Jennifer A.
Weiss, Samuel
Luchman, H. Artee
Cairncross, J. Gregory
Venue: Neuro-Oncology
Publisher: Oxford University Press (OUP)
Published: 2013-12-22
Volume: 16
Issue: 5
Pages: 686-695
ISSN: 1522-8517 (ISSN-L)
1523-5866
DOI: 10.1093/neuonc/not243
PMC: PMC3984548
OpenAlex: W2101246344
Cited by: 210
References: 39
Citations by year: 2026: 16 · 2025: 10 · 2024: 16 · 2023: 13 · 2022: 19 · 2021: 33 · 2020: 22 · 2019: 16 · 2018: 20 · 2017: 12 · 2016: 9 · 2015: 12 · 2014: 11
FWCI: 5.25
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Neuro-Oncology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Cancer Institute (R01CA172845)
Topics: Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords: LDHA, IDH mutation, isocitrate dehydrogenase, glioma, brain tumor stem cells, hypoxia-inducible factor-1α, 2-hydroxyglutarate, DNA methylation, promoter methylation, glycolysis, glioblastoma, Warburg effect, cancer metabolism
MeSH terms: Lactate Dehydrogenase 5, Animals, Glioblastoma, Glioma, Humans, Isocitrate Dehydrogenase, Isoenzymes, L-Lactate Dehydrogenase, Mutation, Gene Expression Regulation, Neoplastic, DNA Methylation, Brain Stem Neoplasms, Gene Silencing, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit

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Lactate dehydrogenase A silencing in IDH mutant gliomas

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