American Association for Cancer Research
Browse
cd-22-0825_supplementary_figure_s2_suppsf2.pdf (256.37 kB)

Supplementary Figure S2 from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers

Download (256.37 kB)
journal contribution
posted on 2023-06-02, 08:21 authored by Kathryn Gunn, Matti Myllykoski, John Z. Cao, Manna Ahmed, Bofu Huang, Betty Rouaisnel, Bill H. Diplas, Michael M. Levitt, Ryan Looper, John G. Doench, Keith L. Ligon, Harley I. Kornblum, Samuel K. McBrayer, Hai Yan, Cihangir Duy, Lucy A. Godley, Peppi Koivunen, Julie-Aurore Losman

Inhibition of KDM5 enzymes by the (R)- and (S)-enantiomers of 2-hydroxyglutarate.

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

Find out more...

Sidney Kimmel Foundation (SKF)

William Guy Forbeck Research Foundation (WGFRF)

Wong Family

Dana-Farber Cancer Institute (DFCI)

History

ARTICLE 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. 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

Usage metrics

    Cancer Discovery

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC