The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases

被引：782
|
作者：
Chowdhury, Rasheduzzaman [1 ]
Yeoh, Kar Kheng [1 ]
Tian, Ya-Min [2 ]
Hillringhaus, Lars [1 ]
Bagg, Eleanor A. [1 ]
Rose, Nathan R. [1 ]
Leung, Ivanhoe K. H. [1 ]
Li, Xuan S. [3 ]
Woon, Esther C. Y. [1 ]
Yang, Ming [1 ]
McDonough, Michael A. [1 ]
King, Oliver N. [1 ]
Clifton, Ian J. [1 ]
Klose, Robert J. [3 ]
Claridge, Timothy D. W. [1 ]
Ratcliffe, Peter J. [2 ]
Schofield, Christopher J. [1 ]
Kawamura, Akane [1 ]
机构：
[1] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England
[2] Univ Oxford, Dept Clin Med, Oxford OX3 7BN, England
[3] Univ Oxford, Dept Biochem, Epigenet Regulat Chromatin Funct Grp, Oxford OX1 3QU, England
来源：
EMBO REPORTS | 2011年 / 12卷 / 05期
基金：
英国生物技术与生命科学研究理事会; 英国惠康基金;
关键词：
isocitrate dehydrogenase; 2-hydroxyglutarate; 2-oxoglutarate; oxygenases; hypoxia-inducible factor; HYPOXIA-INDUCIBLE FACTOR; ISOCITRATE DEHYDROGENASE 1; PROLYL HYDROXYLASE; STRUCTURAL BASIS; MUTATIONS; CANCER; TRANSCRIPTION; SPECIFICITY; HIF-1-ALPHA; METABOLISM;
D O I：
10.1038/embor.2011.43
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Mutations in isocitrate dehydrogenases (IDHs) have a gain-of- function effect leading to R(-)-2-hydroxyglutarate (R-2HG) accumulation. By using biochemical, structural and cellular assays, we show that either or both R-and S-2HG inhibit 2-oxoglutarate (2OG)-dependent oxygenases with varying potencies. Half-maximal inhibitory concentration (IC(50)) values for the R-form of 2HG varied from approximately 25 mu M for the histone N(epsilon)-lysine demethylase JMJD2A to more than 5mM for the hypoxia-inducible factor (HIF) prolyl hydroxylase. The results indicate that candidate oncogenic pathways in IDH-associated malignancy should include those that are regulated by other 2OG oxygenases than HIF hydroxylases, in particular those involving the regulation of histone methylation.
引用
收藏
页码：463 / 469
页数：7
相关论文
共 50 条
  • [1] (R)-2-hydroxyglutarate inhibits KDM5 histone lysine demethylases to drive tumorigenesis in IDH-mutant cancers
    Gunn, Kathryn E.
    Myllykoski, Matti
    Cao, John
    Huang, Bofu
    Rouaisnel, Betty
    Diplas, Bill
    Levitt, Michael M.
    Looper, Ryan
    Doench, John G.
    Ligon, Keith L.
    Kornblum, Harley I.
    Yan, Hai
    McBrayer, Samuel
    Godley, Lucy A.
    Koivunen, Peppi
    Losman, Julie-Aurore
    CANCER RESEARCH, 2022, 82 (12)
  • [2] Quantitative Analysis of Oncometabolite 2-Hydroxyglutarate
    Yuan, Bi-Feng
    CANCER METABOLOMICS: METHODS AND APPLICATIONS, 2021, 1280 : 161 - 172
  • [3] (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers br
    Gunn, Kathryn
    Myllykoski, Matti
    Cao, John Z.
    Ahmed, Manna
    Huang, Bofu
    Rouaisnel, Betty
    Diplass, Bill H.
    Levitt, Michael M.
    Looper, Ryan
    Doench, John G.
    Ligon, Keith L.
    Kornblum, Harley I.
    McBrayers, Samuel K.
    Yan, Hai
    Duy, Cihangir
    Godley, Lucy A.
    Koivunen, Peppi
    Losman, Julie-Aurore
    CANCER DISCOVERY, 2023, 13 (06) : 1478 - 1497
  • [4] The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway
    Mélissa Carbonneau
    Laurence M. Gagné
    Marie-Eve Lalonde
    Marie-Anne Germain
    Alena Motorina
    Marie-Christine Guiot
    Blandine Secco
    Emma E. Vincent
    Anthony Tumber
    Laura Hulea
    Jonathan Bergeman
    Udo Oppermann
    Russell G. Jones
    Mathieu Laplante
    Ivan Topisirovic
    Kevin Petrecca
    Marc-Étienne Huot
    Frédérick A. Mallette
    Nature Communications, 7
  • [5] The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway
    Carbonneau, Melissa
    Gagne, Laurence M.
    Lalonde, Marie-Eve
    Germain, Marie-Anne
    Motorina, Alena
    Guiot, Marie-Christine
    Secco, Blandine
    Vincent, Emma E.
    Tumber, Anthony
    Hulea, Laura
    Bergeman, Jonathan
    Oppermann, Udo
    Jones, Russell G.
    Laplante, Mathieu
    Topisirovic, Ivan
    Petrecca, Kevin
    Huot, Marc-Etienne
    Mallette, Frederick A.
    NATURE COMMUNICATIONS, 2016, 7
  • [6] Oncometabolite 2-hydroxyglutarate impacts metabolism but not function of T cells
    Boettcher, M.
    Renner, K.
    Mentz, K.
    Mackensen, A.
    Kreutz, M.
    Mougiakakos, D.
    ONCOLOGY RESEARCH AND TREATMENT, 2016, 39 : 47 - 47
  • [7] Oncometabolite 2-hydroxyglutarate regulates anti-tumor immunity
    Cai, Mengyuan
    Zhao, Jianyi
    Ding, Qiang
    Wei, Jifu
    HELIYON, 2024, 10 (02)
  • [8] Quantitative analysis of 2-hydroxyglutarate as a controversial oncometabolite in malignant gliomas
    Bystrick, P.
    Kasubova, I
    Richterov, R.
    Lasabov, Z.
    Kolarovszki, B.
    NEOPLASMA, 2020, 67 (06) : 1367 - 1372
  • [9] Roles of the oncometabolite enantiomers of 2-hydroxyglutarate and their metabolism by diverse dehydrogenases
    Garcia, Ivelitza
    Cornely, Kathleen
    Peterson, Celeste N.
    Berkmen, Melanie B.
    ESSAYS IN BIOCHEMISTRY, 2024,
  • [10] Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases
    Xu, Wei
    Yang, Hui
    Liu, Ying
    Yang, Ying
    Wang, Ping
    Kim, Se-Hee
    Ito, Shinsuke
    Yang, Chen
    Wang, Pu
    Xiao, Meng-Tao
    Liu, Li-xia
    Jiang, Wen-qing
    Liu, Jing
    Zhang, Jin-ye
    Wang, Bin
    Frye, Stephen
    Zhang, Yi
    Xu, Yan-hui
    Lei, Qun-ying
    Guan, Kun-Liang
    Zhao, Shi-min
    Xiong, Yue
    CANCER CELL, 2011, 19 (01) : 17 - 30
12345