2. Academic Validation
  3. (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers

(R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers

  • Cancer Discov. 2023 Jun 2;13(6):1478-1497. doi: 10.1158/2159-8290.CD-22-0825.
Kathryn Gunn 1,  Matti Myllykoski 2,  John Z Cao 3,  Manna Ahmed 4,  Bofu Huang 1,  Betty Rouaisnel 1,  Bill H Diplas 5,  Michael M Levitt 6,  Ryan Looper 7,  John G Doench 8,  Keith L Ligon 8 9 10,  Harley I Kornblum 11,  Samuel K McBrayer 6,  Hai Yan 5,  Cihangir Duy 4,  Lucy A Godley 3 12,  Peppi Koivunen 2,  Julie-Aurore Losman 1 13
Affiliations

Affiliations

  • 1 Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 2 Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
  • 3 Committee on Cancer Biology, Biological Sciences Division, University of Chicago, Chicago, Illinois.
  • 4 Cancer Signaling and Epigenetics Program, Cancer Epigenetic Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
  • 5 Department of Pathology, Duke University Medical Center, Durham, North Carolina.
  • 6 Children's Medical Center Research Institute and Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • 7 Department of Chemistry, University of Utah, Salt Lake City, Utah.
  • 8 Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • 9 Department of Pathology, Boston Children's Hospital and Brigham and Women's Hospital, Boston, Massachusetts.
  • 10 Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 11 Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • 12 Section of Hematology/Oncology, Departments of Medicine and Human Genetics, University of Chicago, Chicago, Illinois.
  • 13 Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
PMID: 36847506 DOI: 10.1158/2159-8290.CD-22-0825
Abstract

Oncogenic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in a wide range of cancers, including acute myeloid leukemia (AML) and glioma. Mutant IDH Enzymes convert 2-oxoglutarate (2OG) to (R)-2-hydroxyglutarate [(R)-2HG], an oncometabolite that is hypothesized to promote cellular transformation by dysregulating 2OG-dependent Enzymes. The only (R)-2HG target that has been convincingly shown to contribute to transformation by mutant IDH is the myeloid tumor suppressor TET2. However, there is ample evidence to suggest that (R)-2HG has Other functionally relevant targets in IDH-mutant cancers. Here, we show that (R)-2HG inhibits KDM5 histone lysine demethylases and that this inhibition contributes to cellular transformation in IDH-mutant AML and IDH-mutant glioma. These studies provide the first evidence of a functional link between dysregulation of histone lysine methylation and transformation in IDH-mutant cancers.

Significance: Mutant IDH is known to induce histone hypermethylation. However, it is not known if this hypermethylation is functionally significant or is a bystander effect of (R)-2HG accumulation in IDH-mutant cells. Here, we provide evidence that KDM5 inhibition by (R)-2HG contributes to mutant IDH-mediated transformation in AML and glioma. This article is highlighted in the In This Issue feature, p. 1275.

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