<i>IDH1</i>and<i>IDH2</i>Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives

Yang, Hui; Ye, Dan; Guan, Kun Liang; Xiong, Yue

doi:10.1158/1078-0432.ccr-12-1773

Cited by 350 publications

(329 citation statements)

References 93 publications

(90 reference statements)

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“…PKM2 expression was shown to be involved in early tumorigenesis (28) and can be detected in the blood and stool of cancer patients (9,82); furthermore, increases in PKM2 levels were reported to correlate with tumor size and stage (9). As described in another article in this CCR Focus section by Yang and colleagues, mutations of IDH1 and IDH2 are also reported to be easily detectable using small amounts of tumor samples (83). Accordingly, these enzymes involved in cancer metabolism can be useful biomarkers.…”

Section: Discussionmentioning

confidence: 95%

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

Tamada

Suematsu

Saya

2012

Clinical Cancer Research

203

195

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The M2 splice isoform of pyruvate kinase (PKM2), an enzyme that catalyzes the later step of glycolysis, is a key regulator of aerobic glycolysis (known as the Warburg effect) in cancer cells. Expression and low enzymatic activity of PKM2 confer on cancer cells the glycolytic phenotype, which promotes rapid energy production and flow of glycolytic intermediates into collateral pathways to synthesize nucleic acids, amino acids, and lipids without the accumulation of reactive oxygen species. PKM2 enzymatic activity has also been shown to be negatively regulated by the interaction with CD44 adhesion molecule, which is a cell surface marker for cancer stem cells. In addition to the glycolytic functions, nonglycolytic functions of PKM2 in cancer cells are of particular interest. PKM2 is induced translocation into the nucleus, where it activates transcription of various genes by interacting with and phosphorylating specific nuclear proteins, endowing cancer cells with a survival and growth advantage. Therefore, inhibitors and activators of PKM2 are well underway to evaluate their anticancer effects and suitability for use as novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 95%

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

Tamada

Suematsu

Saya

2012

Clinical Cancer Research

203

195

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“…Isocitrate dehydrogenase 1 and 2, IDH1 and IDH2, were surprising additions to the list of cancer drivers emerging from glioblastoma multiforme (GBM) among the first whole-exome screens reported (Parsons et al 2008). Both enzymes normally convert isocitrate to a-ketoglutarate (a-KG), a cofactor for a-KG dioxygenases, including TET family DNA demethylases, KDM-family histone demethylases, and many other proteins (Yang et al 2012). Mutated IDH1/2 both produce 2-oxyglutarate, a structural analog of a-KG but potent inhibitor of a-KG-dependent enzymes, the methyltransferases involved in DNA and chromatin methylation.…”

Section: Novel High-frequency Cancer Genesmentioning

confidence: 99%

From human genome to cancer genome: The first decade

2013

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The realization that cancer progression required the participation of cellular genes provided one of several key rationales, in 1986, for embarking on the human genome project. Only with a reference genome sequence could the full spectrum of somatic changes leading to cancer be understood. Since its completion in 2003, the human reference genome sequence has fulfilled its promise as a foundational tool to illuminate the pathogenesis of cancer. Herein, we review the key historical milestones in cancer genomics since the completion of the genome, and some of the novel discoveries that are shaping our current understanding of cancer.

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“…IDH1 is located in the cytosol and peroxisomes, while IDH2 and IDH3 are located in mitochondria. IDH1 and IDH2 use NADP + as a cofactor, while IDH3 uses NAD + as a cofactor in the TCA cycle for energy metabolism [33].…”

Section: Idh1 and Idh2 Are Most Frequently Mutated Metabolic Genes Inmentioning

confidence: 99%

Metabolic alteration in tumorigenesis

Yang

Guan

2013

Sci. China Life Sci.

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Altered metabolism in cancer was first discovered by Otto Warburg early last century. Although the Warburg Effect has been widely used in tumor detection, relatively little progress had been made in mechanistic understanding of cancer metabolism in the subsequent eight decades. Genetic studies have recently identified mutations in human cancer targeting multiple enzymes involved in intermediate metabolism. One emerging mechanism common to these mutant enzymes is the accumulation of a metabolite that alters the epigenetic control. Otto Warburg [1,2] first discovered that cancer cells displayed enhanced glucose uptake and aerobic glycolysis, a phenomenon often referred as the Warburg Effect nowadays. Although the mechanism underlying the Warburg Effect is still not fully understood, increased uptake of glucose provides the basis to exploit its clinical application by 18 F-deoxyglucose positron emission tomography (PET) for tumor detection [3,4]. Decades after the Warburg Effect was discovered, the mechanistic insights of how metabolic alterations contribute to tumorigenesis are just emerging. Recent studies have revealed that eight metabolic genes, FH, SDHA, SDHB, SDHC, SDHD, SDHAF2, IDH1 and IDH2, encoding for subunits of four different metabolic enzymes, fumarate hydratase (FH), succinate dehydrogenase (SDH), and isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), were mutated in a number of human cancers [5]. These findings provide compelling genetic evidence supporting the notion that altered metabolism contributes to, as opposed to the consequence of, tumorigenesis. Here, we first briefly discuss how metabolism is reprogrammed to support cancer cell proliferation. We then focus on one emerging mechanism that is common to the mutations targeting all four metabolic enzymes in accumulating a metabolite to alter the epigenetic modifications in human cancer.

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IDH1andIDH2Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives

Cited by 350 publications

References 93 publications

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

From human genome to cancer genome: The first decade

Metabolic alteration in tumorigenesis

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