(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
  • 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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