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  • In C elegans KDM A appears to be involved in

    2022-05-27

    In C. elegans, KDM4A appears to be involved in H3K36me3 reduction on the X chromosome, suggesting that this protein has a relevant role in germ cell development (Figure 2A) (47). In addition, in HeLa cells, KDM4A is associated with the repression of the achaete-scute complex homologue 2 (ASCL2) gene by acting as a cofactor of the nuclear receptor corepressor (N-CoR); this function requires its demethylase activity 18, 41. KDM4A also interacts with histone deacetylases (HDACs) and retinoblastoma protein (pRb); this partnership is involved in the repression of E2F-dependent promoters (Figure 2A). However, the role of this protein as a demethylase has not been studied in this context (42). Remarkably, H3K9me3 demethylation of the myogenin (myogenic factor 4, or Myog) gene promoter during skeletal muscle differentiation of myoblasts into myotubes is performed by a ΔN-KDM4A isoform (Figure 2D) (43). These data suggest that functional KDM4A isoforms might also play a major role in the regulation of gene expression. Genes repressed or activated by Drosophila melanogaster KDM4A (dKDM4A) were reported to not require KDM4A catalytic activity for expression; nevertheless, activated genes require its demethylase activity for proper expression (44). These findings suggest that some of these genes are indirect dKDM4A targets and that epigenetic regulation can be either dependent on or independent of the demethylase catalytic activity (44). One study demonstrated that some dKDM4A-regulated genes were near one another, suggesting that genes controlled by this enzyme may require a common Enalapril Maleate environment (44). Interestingly, chromatin immunoprecipitation (ChIP) assays showed that the H3K36me3 levels were very low in both wild types and dKDM4A mutants (P/DdKDM4A) and that no detectable amounts of H3K9me3 were present in either wild types or mutants. These results indicate that many of the dKDM4A-controlled genes are modulated not by these histone marks but by other dKDM4A-dependent functions. A likely explanation for the changes found in mutants may be that they are due to the interaction of KDM4A with other proteins, such as pRb and N-CoR (Figure 2A) 41, 42, 43, 44. Histone modifications are important in chromatin structure. Global and local chromatin architecture alterations are common findings in tumors 54, 55. The expression pattern of KDM4A has been suggested to be altered in several cancer types that involve such chromatin modifications. Here, we summarize some aspects of the role of KDM4A in cancer development.
    The role of KDM4A in cancer development
    KDM4A as a potential therapeutic target Many histone demethylase inhibitors have been described; these inhibitors can be classified into five groups: iron chelators, α-ketoglutarate analogues, catalytic site inhibitors, prodrugs, and zinc chelators (Table 2) 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104. However, the lack of research on the selectivity and specificity of histone demethylases and thus the deficiency of our knowledge regarding nondesirable targets have prevented these inhibitors from progressing toward clinical research. Therefore, the use of such inhibitors remains in the preclinical phase (105). These reported inhibitors include N-oxalylglycine (NOG) and its derivatives, which are analogues of the cosubstrate α-ketoglutarate. They inhibit KDM4A and other members of the KDM4 family via competition. In addition, another analogue of α-ketoglutarate is the oncometabolite 2-hydroxyglutarate, which also inhibits KDM4 enzymes by competition but is a weak antagonist of α-ketoglutarate 92, 93, 94. However, these chemicals are not very specific, because they target different α-ketoglutarate-dependent enzymes 92, 93, 94. Another molecule that has inhibitory action is pyrimidine 2,4-dicarboxylic acid, whose mechanism of action is based on electrostatic interactions with a lysine residue within the active site; nevertheless, little is known about its uses in therapy (105). Additionally, hydroxamic acid and its derivatives, such as trichostatin A, most likely function as iron chelators to inhibit the catalytic activity of JmjC domain-containing demethylases such as KDM4A (65). Moreover, the main use of these compounds is against HDACs (106); therefore, the probable side effects make the future development of this class of compounds unpromising (105).