Isocitrate Dehydrogenase Mutations in Cancer: Mechanisms of Transformation and Metabolic Liability.
Cold Spring Harb Perspect Med
; 14(5)2024 05 02.
Article
em En
| MEDLINE
| ID: mdl-38191174
ABSTRACT
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are metabolic enzymes that interconvert isocitrate and 2-oxoglutarate (2OG). Gain-of-function mutations in IDH1 and IDH2 occur in a number of cancers, including acute myeloid leukemia, glioma, cholangiocarcinoma, and chondrosarcoma. These mutations cripple the wild-type activity of IDH and cause the enzymes to catalyze a partial reverse reaction in which 2OG is reduced but not carboxylated, resulting in production of the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). (R)-2HG accumulation in IDH-mutant tumors results in profound dysregulation of cellular metabolism. The most well-characterized oncogenic effects of (R)-2HG involve the dysregulation of 2OG-dependent epigenetic tumor-suppressor enzymes. However, (R)-2HG has many other effects in IDH-mutant cells, some that promote transformation and others that induce metabolic dependencies. Herein, we review how cancer-associated IDH mutations impact epigenetic regulation and cellular metabolism and discuss how these effects can potentially be leveraged to therapeutically target IDH-mutant tumors.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Isocitrato Desidrogenase
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Mutação
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Neoplasias
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cold Spring Harb Perspect Med
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos