Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7

Gerken, Philip A.; Wolstenhulme, Stephen; Tumber, Anthony; Hatch, Stephanie B.; Zhang, Yijia; Müller, Susanne; Chandler, Shane A.; Mair, Barbara; Li, Fengling; Nijman, Sebastian M.; Konietzny, Rebecca; Szommer, Tamás; Yapp, Clarence; Fedorov, Oleg; Benesch, Justin L. P.; Vedadi, Masoud; Kessler, Benedikt M.; Kawamura, Akane; Brennan, P.E.; Smith, Martin D.

doi:10.1002/anie.201706788

Cited by 35 publications

(22 citation statements)

References 45 publications

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“…SPE-MS requires only small amounts of substrates/enzymes for analysis and has been successfully applied to monitoring the activity of 2OG oxygenases by measuring mass shifts, i.e. +16 Da for hydroxylation and -14 Da for demethylation (41)(42)(43)(44)(45). We aimed to combine SPE-MS with the use of stable substrate analogues in which the non-canonical Cys 3-4 EGFD disulfide bond was replaced with a stable thioether.…”

Section: Development Of An Efficient Asph Activity Assaymentioning

confidence: 99%

Kinetic parameters of human aspartate/asparagine–β-hydroxylase suggest that it has a possible function in oxygen sensing

Brewitz

Tumber

Schofield

2020

Journal of Biological Chemistry

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Human aspartate/asparagine–β-hydroxylase (AspH) is a 2-oxoglutarate (2OG)–dependent oxygenase that catalyzes the post-translational hydroxylation of Asp and Asn residues in epidermal growth factor–like domains (EGFDs). Despite its biomedical significance, studies on AspH have long been limited by a lack of assays for its isolated form. Recent structural work has revealed that AspH accepts substrates with a noncanonical EGFD disulfide connectivity (i.e. the Cys 1–2, 3–4, 5–6 disulfide pattern). We developed stable cyclic thioether analogues of the noncanonical EGFD AspH substrates to avoid disulfide shuffling. We monitored their hydroxylation by solid-phase extraction coupled to MS. The extent of recombinant AspH-catalyzed cyclic peptide hydroxylation appears to reflect levels of EGFD hydroxylation observed in vivo, which vary considerably. We applied the assay to determine the kinetic parameters of human AspH with respect to 2OG, Fe(II), l-ascorbic acid, and substrate and found that these parameters are in the typical ranges for 2OG oxygenases. Of note, a relatively high Km for O2 suggested that O2 availability may regulate AspH activity in a biologically relevant manner. We anticipate that the assay will enable the development of selective small-molecule inhibitors for AspH and other human 2OG oxygenases.

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Section: Development Of An Efficient Asph Activity Assaymentioning

confidence: 99%

Kinetic parameters of human aspartate/asparagine–β-hydroxylase suggest that it has a possible function in oxygen sensing

Brewitz

Tumber

Schofield

2020

Journal of Biological Chemistry

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“…However, the lack of ideal inhibitors to KDM2A limits the potential amplification of KDM2A-based therapy. Recent discovery of highly selective inhibitor of KDM2A might provide opportunities to develop KDM2A targeted therapy for lung cancer [ 107 ].…”

Section: Kdms and Their Roles In Lung Cancermentioning

confidence: 99%

Lung Cancer Therapy Targeting Histone Methylation: Opportunities and Challenges

Chen

Liu

et al. 2018

Computational and Structural Biotechnology Journal

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Lung cancer is one of the most common malignancies. In spite of the progress made in past decades, further studies to improve current therapy for lung cancer are required. Dynamically controlled by methyltransferases and demethylases, methylation of lysine and arginine residues on histone proteins regulates chromatin organization and thereby gene transcription. Aberrant alterations of histone methylation have been demonstrated to be associated with the progress of multiple cancers including lung cancer. Inhibitors of methyltransferases and demethylases have exhibited anti-tumor activities in lung cancer, and multiple lead candidates are under clinical trials. Here, we summarize how histone methylation functions in lung cancer, highlighting most recent progresses in small molecular inhibitors for lung cancer treatment.

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“…Prior studies, based on either single-locus or genome-wide gene expression analysis, have suggested that KDM7A is involved in the regulation of target genes downstream of the NF-κB pathway ( Higashijima et al, 2020 ) and the Wnt/β-catenin pathway ( Yang et al, 2019a ; Liu et al, 2020 ), which allude to a broader promalignancy mechanism. Small-molecule inhibitors of KDM7A have been discovered although their therapeutic potentials in breast cancer have yet to be explored ( Gerken et al, 2017 ). Our report as summarized here undoubtedly provides a strong rationale for considering these compounds as a viable treatment option for the most malignant forms of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells

Zhang

Chen

Zhu

et al. 2021

Front. Cell Dev. Biol.

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The small GTPase RHOJ is a key regulator of breast cancer metastasis by promoting cell migration and invasion. The prometastatic stimulus TGF-β activates RHOJ transcription via megakaryocytic leukemia 1 (MKL1). The underlying epigenetic mechanism is not clear. Here, we report that MKL1 deficiency led to disrupted assembly of the RNA polymerase II preinitiation complex on the RHOJ promoter in breast cancer cells. This could be partially explained by histone H3K9/H3K27 methylation status. Further analysis confirmed that the H3K9/H3K27 dual demethylase JHDM1D/KDM7A was essential for TGF-β-induced RHOJ transcription in breast cancer cells. MKL1 interacted with and recruited KDM7A to the RHOJ promoter to cooperatively activate RHOJ transcription. KDM7A knockdown attenuated migration and invasion of breast cancer cells in vitro and mitigated the growth and metastasis of breast cancer cells in nude mice. KDM7A expression level, either singularly or in combination with that of RHOJ, could be used to predict prognosis in breast cancer patients. Of interest, KDM7A appeared to be a direct transcriptional target of TGF-β signaling. A SMAD2/SMAD4 complex bound to the KDM7A promoter and mediated TGF-β-induced KDM7A transcription. In conclusion, our data unveil a novel epigenetic mechanism whereby TGF-β regulates the transcription of the prometastatic small GTPase RHOJ. Screening for small-molecule inhibitors of KDM7A may yield effective therapeutic solutions to treat malignant breast cancers.

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Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7

Cited by 35 publications

References 45 publications

Kinetic parameters of human aspartate/asparagine–β-hydroxylase suggest that it has a possible function in oxygen sensing

Kinetic parameters of human aspartate/asparagine–β-hydroxylase suggest that it has a possible function in oxygen sensing

Lung Cancer Therapy Targeting Histone Methylation: Opportunities and Challenges

The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells

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