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Related Concept Videos

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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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(R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers.

Kathryn Gunn1, Matti Myllykoski2, John Z Cao3

  • 1Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

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|February 27, 2023
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Summary

Mutant isocitrate dehydrogenase (IDH) enzymes create an oncometabolite that drives cancer. This study reveals that (R)-2-hydroxyglutarate inhibits KDM5 demethylases, contributing to IDH-mutant AML and glioma transformation.

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Area of Science:

  • Biochemistry
  • Cancer Biology
  • Epigenetics

Background:

  • Oncogenic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are prevalent in various cancers, including acute myeloid leukemia (AML) and glioma.
  • Mutant IDH enzymes produce (R)-2-hydroxyglutarate [(R)-2HG], an oncometabolite that disrupts 2-oxoglutarate (2OG)-dependent enzymes, potentially promoting cancer.
  • While TET2 is a known (R)-2HG target, other targets likely contribute to transformation in IDH-mutant cancers.

Purpose of the Study:

  • To investigate the functional targets of (R)-2HG in IDH-mutant cancers.
  • To determine if inhibition of KDM5 histone lysine demethylases by (R)-2HG contributes to cellular transformation in IDH-mutant AML and glioma.

Main Methods:

  • Investigated the effect of (R)-2HG on KDM5 histone lysine demethylases.
  • Assessed the contribution of KDM5 inhibition to cellular transformation in IDH-mutant AML and glioma models.

Main Results:

  • Demonstrated that (R)-2HG directly inhibits KDM5 histone lysine demethylases.
  • Provided evidence that this inhibition is a significant factor in the cellular transformation of IDH-mutant AML and glioma.
  • Established a functional link between histone lysine methylation dysregulation and cancer transformation in IDH-mutant contexts.

Conclusions:

  • The inhibition of KDM5 demethylases by (R)-2HG is a key mechanism driving transformation in IDH-mutant cancers.
  • This finding reveals a novel link between epigenetic dysregulation (histone methylation) and oncogenesis in IDH-mutant AML and glioma.