University of Oulu

Tuomas Laukka, Matti Myllykoski, Ryan E. Looper, Peppi Koivunen, Cancer-associated 2-oxoglutarate analogues modify histone methylation by inhibiting histone lysine demethylases, Journal of Molecular Biology, Volume 430, Issue 18, Part B, 2018, Pages 3081-3092, ISSN 0022-2836, https://doi.org/10.1016/j.jmb.2018.06.048

Cancer-associated 2-oxoglutarate analogues modify histone methylation by inhibiting histone lysine demethylases

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Author: Laukka, Tuomas1; Myllykoski, Matti1; Looper, Ryan E.2;
Organizations: 1Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland
2Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 1.1 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe201901081623
Language: English
Published: Elsevier, 2018
Publish Date: 2019-07-05
Description:

Abstract

Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. Their dysregulation has been associated with many cancers. We set out to study the catalytic and inhibitory properties of human KDM4A, KDM4B, KDM5B, KDM6A and KDM6B, aiming in particular to reveal which of these enzymes are targeted by cancer-associated 2-oxoglutarate (2-OG) analogues. We used affinity-purified insect cell-produced enzymes and synthetic peptides with trimethylated lysines as substrates for the in vitro enzyme activity assays. In addition, we treated breast cancer cell lines with cell-permeable forms of 2-OG analogues and studied their effects on the global histone methylation state. Our data show that KDMs have substrate specificity. Among the enzymes studied, KDM5B had the highest affinity for the peptide substrate but the lowest affinity for the 2-OG and the Fe2+ cosubstrate/cofactors. R-2-hydroxyglutarate (R-2HG) was the most efficient inhibitor of KDM6A, KDM4A and KDM4B, followed by S-2HG. This finding was supported by accumulations of the histone H3K9me3 and H3K27me3 marks in cells treated with the cell-permeable forms of these compounds. KDM5B was especially resistant to inhibition by R-2HG, while citrate was the most efficient inhibitor of KDM6B. We conclude that KDM catalytic activity is susceptible to inhibition by tumorigenic 2-OG analogues and suggest that the inhibition of KDMs is involved in the disease mechanism of cancers in which these compounds accumulate, such as the isocitrate dehydrogenase mutations.

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Series: Journal of molecular biology
ISSN: 0022-2836
ISSN-E: 1089-8638
ISSN-L: 0022-2836
Volume: 430
Issue: 18
Pages: 3081 - 3092
DOI: 10.1016/j.jmb.2018.06.048
OADOI: https://oadoi.org/10.1016/j.jmb.2018.06.048
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
KDM
Funding: This work was supported by Academy of Finland Grants 266719 and 308009 (P.K.), and by grants from the S. Jusélius Foundation (P.K.), the Emil Aaltonen Foundation (P.K. and T.L.), the Finnish Medical Foundation (T.L.), the Jane and Aatos Erkko Foundation (P.K.) and the Finnish Cancer Organizations (P.K.).
Academy of Finland Grant Number: 266719
308009
Detailed Information: 266719 (Academy of Finland Funding decision)
308009 (Academy of Finland Funding decision)
Copyright information: © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
  https://creativecommons.org/licenses/by-nc-nd/4.0/