The emerging roles of lysine-specific demethylase 4A in cancer: Implications in tumorigenesis and therapeutic opportunities

Yang, Guan–Jun; Li, Changyun; Fan, Tao; Liu, Yanjun; Zhu, Min; Du, Yong; Fei, Chenjie; She, Qiusheng; Chen, Jiong

doi:10.1016/j.gendis.2022.12.020

Cited by 9 publications

(2 citation statements)

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“…Some enzymes such as Jumonji C (JmjC) demethylases, ten-eleven-translocation (TET) enzymes, COX2, and HDACs are also metalloproteases and are invlvoled in modulating several chronic inflammatory diseases [( 5 , 7 ), Jin et al. and Wang et al.…”

Section: Othersmentioning

confidence: 99%

“…Mutiple chronic inflammatory diseases could even hijack various metalloproteases to promote and exacerbate inflammation ( 1 , 2 ). Numerous preclinical and clinical studies have shown that metalloprotease modulators, including lysine-specific demethyalses (KDMs) inhibitors ( 3 – 5 , 7 ), histone deacetylases (HDACs) inhibitors ( 8 ), and matrix metalloproteinases (MMPs) inhibitors ( 6 ), and a disintegrin and metalloproteinases (ADAMs) inhibitors ( 9 ), possess in vitro and in vivo anti–inflammatory activities. Therefore, understanding the roles of metalloproteinases in the immune system may potenitally uncover new targets for the diagnosis and treatment of chronic inflammatory diseases.…”

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confidence: 99%

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Editorial: Immunomodulatory role of metalloproteases in chronic inflammatory diseases

Yang

et al. 2023

Front. Immunol.

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Editorial on the Research TopicImmunomodulatory role of metalloproteases in chronic inflammatory diseases Metalloproteases are a diverse class of enzymes involved in the regulation of numerous pathological and physiological processes. Evidence has shown that metalloproteases could either directly or indirectly regulate the secretion of chemokines and the differentiation and/or activation of immune cells, thereby mediating many inflammatory and innate immune responses (1, 2). While different metalloproteases could have substantially different primary structure, their active center which contains metal ions (e.g. iron, zinc, cobalt, nickel ions) is relatively conservative. Metalloprotease relies on metal ions to maintain its catalytic function. Studies have shown that metal chelators such as EDTA could completely inactivate metalloproteases (3-6; Liu et al.). Under inflammatory conditions, metalloproteases are constitutively activated or deactivated in multiple immune-or non-immune cells and could contribute to a variety of inflammatory diseases, such as rheumatoid arthritis (RA) (Li et al.), chronic enteritis (Deng et al. and Mei et al.), allergic dieseases (Wang and Wang and Bendavid et al.), diabetes (Chen et al.), and cancers (He et al.), etc. Mutiple chronic inflammatory diseases could even hijack various metalloproteases to promote and exacerbate inflammation (1, 2). Numerous preclinical and clinical studies have shown that metalloprotease modulators, including lysine-specific demethyalses (KDMs) inhibitors (3-5, 7), histone deacetylases (HDACs) inhibitors (8), and matrix metalloproteinases (MMPs) inhibitors (6), and a disintegrin and metalloproteinases (ADAMs) inhibitors (9), possess in vitro and in vivo anti-inflammatory activities. Therefore, understanding the roles of metalloproteinases in the immune system may potenitally uncover new targets for the diagnosis and treatment of chronic inflammatory diseases.

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Section: Othersmentioning

confidence: 99%

mentioning

confidence: 99%

Editorial: Immunomodulatory role of metalloproteases in chronic inflammatory diseases

Yang

et al. 2023

Front. Immunol.

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Origins of Catalysis in Non‐Heme Fe(II)/2‐Oxoglutarate‐Dependent Histone Lysine Demethylase KDM4A with Differently Methylated Histone H3 Peptides

Devadas,

Thomas,

Rifayee

et al. 2024

Chemistry A European J

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Histone lysine demethylase 4A (KDM4A), a non‐heme Fe(II)/2‐oxoglutarate (2OG) dependent oxygenase that catalyzes the demethylation of tri‐methylated lysine residues at the 9, 27, and 36 positions of histone H3 (H3K9me3, H3K27me3, and H3K36me3). These methylated residues show contrasting transcriptional roles; therefore, understanding KDM4A’s catalytic mechanisms with these substrates is essential to explain the factors that control the different sequence‐dependent demethylations. In this study, we use molecular dynamics (MD)‐based combined quantum mechanics/molecular mechanics (QM/MM) methods to investigate determinants of KDM4A catalysis with H3K9me3, H3K27me3 and H3K36me3 substrates. In KDM4A‐H3(5‐14)K9me3 and KDM4A‐H3(23‐32)K27me3 ferryl complexes, the O‐H distance positively correlates with the activation barrier of the rate‐limiting step, however in the KDM4A‐H3(32‐41)K36me3, no direct one‐to‐one relationship was found implying that the synergistic effects between the geometric parameters, second sphere interactions and the intrinsic electric field contribute for the effective catalysis for this substrate. The intrinsic electric field along the Fe‐O bond changes between the three complexes and shows a positive correlation with the HAT activation barrier, suggesting that modulating electric field can be used for fine engineering KDM catalysis with a specific substrate. The results reveal how KDM4A uses a combination of strategies to enable near equally efficient demethylation of different H3Kme3 residues.

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Targeting N‐Methyl‐lysine Histone Demethylase KDM4 in Cancer: Natural Products Inhibitors as a Driving Force for Epigenetic Drug Discovery

Cursaro,

Milioni,

Eslami

et al. 2024

ChemMedChem

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KDM4A‐F enzymes are a subfamily of histone demethylases containing the Jumonji C domain (JmjC) using Fe(II) and 2‐oxoglutarate for their catalytic function. KDM4 enzymes are overexpressed or deregulated in cancer, thus leading to alteration in chromatin structure and transcriptional defects. As KDM4 enzymes have been associated with malignancy, they may represent novel targets for developing innovative therapeutic tools to treat different solid and blood tumors, of note, KDM4A is the isozyme most frequently associated with aggressive phenotypes of these tumors. To this aim, industrial and academic medicinal chemistry efforts have identified different KDM4 inhibitors. In most cases, these are pan‐KDM4 inhibitors, with low selectivity against other Jumonji family members. The pharmacophoric features of the inhibitors frequently include a chelating group capable of coordinating the catalytic iron within the active site of the KDM4 enzyme. Nonetheless, non‐chelating compounds have also demonstrated promising inhibitory activity, suggesting potential flexibility in the drug design. Several natural products, containing monovalent or bivalent chelators, have been identified as KDM4 inhibitors, albeit with a micromolar inhibition potency. This highlights the potential for leveraging them as templates for the design and synthesis of new derivatives, exploiting nature’s chemical diversity to pursue more potent and selective KDM4 inhibitors.

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The emerging roles of lysine-specific demethylase 4A in cancer: Implications in tumorigenesis and therapeutic opportunities

Cited by 9 publications

References 173 publications

Editorial: Immunomodulatory role of metalloproteases in chronic inflammatory diseases

Editorial: Immunomodulatory role of metalloproteases in chronic inflammatory diseases

Origins of Catalysis in Non‐Heme Fe(II)/2‐Oxoglutarate‐Dependent Histone Lysine Demethylase KDM4A with Differently Methylated Histone H3 Peptides

Targeting N‐Methyl‐lysine Histone Demethylase KDM4 in Cancer: Natural Products Inhibitors as a Driving Force for Epigenetic Drug Discovery

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