Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer

Jun Koseki, Hugh Colvin, Takahito Fukusumi, Naohiro Nishida, Masamitsu Konno, Koichi Kawamoto, Kenta Tsunekuni, Hidetoshi Matsui, Yuichiro Doki, Masaki Mori, Hideshi Ishii

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Bioinformatics and computational modeling offer innovative approaches to investigate cancer metabolism and predict the secondary and tertiary cellular responses. Dysregulation of metabolism has also been implicated in the pathophysiology of cancer. A significant proportion of patients with glioblastoma and hematological malignancies harbor the mutated forms of the oxidative phosphorylation (OxPhos) enzymes, isocitrate dehydrogenase (IDH) 1 or 2. The mutated forms of IDH1 and IDH2 produce an oncogenic metabolite, D-2-hydroxyglutarate (D2HG). A recent study of breast cancer patients showed that D2HG can also be produced in the absence of mutated IDH, through an alternative route involving over-activated MYC signaling. We developed a novel methodology to computationally analyze gene expression in colorectal cancer (CRC), and identified novel sets of genes that are associated with patient survival. The study of OxPhos-related genes revealed that an imbalance between the expression of IDH1 and IDH2, defined as overexpression of one isoform in relation to the other, was associated with worse prognosis in CRC patients. This effect was further accentuated by reduced expression of the β-oxygenation enzyme, 3-D-hydroxyacyl-CoA dehydratase (HCDH) 4, which has been reported to contribute to metabolism of intracellular D2HG. The present computational analysis revealed a novel and potential mechanism of CRC development, through overproduction of D2HG when there is an imbalance between IDH1 and IDH2 expression, resulting in decreased clearance of D2HG when the β-oxidization pathway is diminished. Additional validation analysis with another gene expression dataset resulted in IDH1/2 imbalanced expression with a shorter DFS compared with balanced expression. Altogether, these findings provide a strong rationale for studying this mechanism further in order to discover novel therapeutic targets for the treatment of CRC.

元の言語英語
ページ(範囲)1181-1191
ページ数11
ジャーナルInternational journal of oncology
46
発行部数3
DOI
出版物ステータス出版済み - 3 1 2015

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

フィンガープリント Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

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    Koseki, J., Colvin, H., Fukusumi, T., Nishida, N., Konno, M., Kawamoto, K., Tsunekuni, K., Matsui, H., Doki, Y., Mori, M., & Ishii, H. (2015). Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer. International journal of oncology, 46(3), 1181-1191. https://doi.org/10.3892/ijo.2015.2833