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IDH3? regulates one-carbon metabolism in glioblastoma.

ABSTRACT: Mutation or transcriptional up-regulation of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) promotes cancer progression through metabolic reprogramming and epigenetic deregulation of gene expression. Here, we demonstrate that IDH3?, a subunit of the IDH3 heterotetramer, is elevated in glioblastoma (GBM) patient samples compared to normal brain tissue and promotes GBM progression in orthotopic glioma mouse models. IDH3? loss of function reduces tricarboxylic acid (TCA) cycle turnover and inhibits oxidative phosphorylation. In addition to its impact on mitochondrial energy metabolism, IDH3? binds to cytosolic serine hydroxymethyltransferase (cSHMT). This interaction enhances nucleotide availability during DNA replication, while the absence of IDH3? promotes methionine cycle activity, S-adenosyl methionine generation, and DNA methylation. Thus, the regulation of one-carbon metabolism via an IDH3?-cSHMT signaling axis represents a novel mechanism of metabolic adaptation in GBM.

SUBMITTER: May JL

PROVIDER: S-EPMC6314828 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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IDH3α regulates one-carbon metabolism in glioblastoma.

May Jasmine L JL Kouri Fotini M FM Hurley Lisa A LA Liu Juan J Tommasini-Ghelfi Serena S Ji Yanrong Y Gao Peng P Calvert Andrea E AE Lee Andrew A Chandel Navdeep S NS Davuluri Ramana V RV Horbinski Craig M CM Locasale Jason W JW Stegh Alexander H AH

Science advances 20190102 1

Mutation or transcriptional up-regulation of isocitrate dehydrogenases 1 and 2 (<i>IDH1</i> and <i>IDH2</i>) promotes cancer progression through metabolic reprogramming and epigenetic deregulation of gene expression. Here, we demonstrate that IDH3α, a subunit of the IDH3 heterotetramer, is elevated in glioblastoma (GBM) patient samples compared to normal brain tissue and promotes GBM progression in orthotopic glioma mouse models. IDH3α loss of function reduces tricarboxylic acid (TCA) cycle turn ...[more]

PMID: 30613765

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Project description:BackgroundLung cancer remains the major cause of cancer related death worldwide. The discovery of targeted therapies against activating mutations in genes like EGFR considerably improved the prognosis for a subgroup of patients but still leaves a large part without a targeted therapy. One carbon metabolism (1CM) has been investigated in several cancer entities and its increased activity has been linked to higher tumor aggressiveness and reduced prognosis. In spite of 1CM enzymes role and correlation to cancer cells progression, comprehensive analysis for the diagnostic and functional role of the complete 1CM enzymes in lung cancer has not been conducted so far.MethodsWe investigated the prognostic and functional relevance of five major 1CM factors (MTHFD2, PGDH3, SHMT2, MTHFD1 and TYMS) in the three major subclasses of lung cancer [pulmonary adenocarcinoma (AC), squamous cell lung cancer (SQCLC) and small cell lung cancer (SCLC)]. We analyzed 1CM enzymes expression and clinicopathological correlation in patient derived tissue samples of 103 AC, 183 SQCLC and 37 SCLC patients by immunohistochemistry. Furthermore, the effect of 1CM enzymes expression on lung cancer cell proliferation and the response to chemotherapy was investigated in 15 representative AC, SQCLC and SCLC cell lines.ResultsExpression of MTHFD2 and PGDH3 was significantly correlated to a worse overall survival only in AC patients. Cell proliferation assays resolved that all 1CM enzymes have a significant impact on cell growth in AC cell lines and are partially involved in cell proliferation in SQCLC and SCLC cell lines. In addition, expression of MTHFD2 correlated significantly with an increased pemetrexed chemoresistance.ConclusionsExpression of MTHFD2 significantly reduces the prognosis of AC patients. Furthermore, MTHFD2 expression is crucial for survival of AC cell lines and its expression correlates with resistance against Pemetrexed. As MTHFD2 is almost not expressed in healthy adult tissue, we therefore suggest that the inhibition of MTHFD2 might be a potential therapeutic strategy to surround pemetrexed resistance in AC.

Dataset Information

IDH3? regulates one-carbon metabolism in glioblastoma.

Publications

IDH3α regulates one-carbon metabolism in glioblastoma.

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