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  • Pyridoxine HCl EZH interaction with HADC and HDAC through th

    2021-09-22

    EZH2 interaction with HADC1 and HDAC2 through the EED subunit is known to recruit histone deacetylases [113,114]. Given that PRC2-mediated repression of transcription may be partly dependent on the function of HDACs in specific cell contexts [115], the leukemia cell treatment with hydroxamic Pyridoxine HCl analogue pan-HDAC inhibitors (HA-HDI), results in decreased PRC2 components and downregulated HMTase activity of EZH2 leading to lower level of H3K27di and tri- methylation [116]. PRC2-mediated recruitment of HDACs to H3K27 [117], can also promote acetylation of H3K27 following depletion of the PRC2 components by HA-HDI and/or siRNA [116]. Because of multi subunit construction of the PRC2 complex, new strategies for targeting EZH2 would comprise novel designs including inhibition of critical subunit interactions and/or EZH2 active site. In recent works, intervention with the interaction between EZH2 and the other PRC2 proteins has emerged to be a more potent specific therapeutic approach in various tumors. Stabilized alpha-helix of EZH2 (SAH-EZH2) peptides are able to disrupt molecular interactions of the PRC2 complex through which decrease the EZH2 protein thereby leading to decreased activity of histone methylation which induce growth inhibition and differentiation in MLL-AF9 leukemic cells [118]. Similarly, Astemizole is a small inhibitor that prevents EZH2 binding to EED in a competitive manner and can contribute to cell cycle arrest in lymphoma cells [119]. Given that DZNep is a non-specific inhibitor of EZH2, which limits its clinical use, and that GSK343 a highly selective inhibitor of EZH2 also display selectivity against EZH1, still effort is under way to identify new molecules able to target EZH2 and no FDA approved drug have been developed in hematopoietic malignancies [120]. Therefore, development of new strategies through modulation of miRNAs implicated in suppression or enhancement of EZH2 may open new opportunities in therapeutic modalities for cancer.
    MiRNA-mediated regulation of EZH2 in leukemia Recently miRNAs (miR) have been known to play key roles in regulating EZH2. miRNAs are a large class of conserved regulatory RNAs that participate in translational repression of messenger RNA controlling target gene expression [121]. Growing evidences have indicated defects in miRNA in different tumor types in human that are linked to patient’s survival and disease outcome [122,123]. miRNAs have emerged to exert either oncogenic or tumor suppressor function and appear to have important roles in cancer development [124]. It has been reported that miR-101 functions as a tumor suppressor in non-small cell lung cancer (NSCLC) and suppresses the expression of EZH2 via binding to 3´-UTR end of EZH2 in NSCLC cells [125]. Similarly, downregulation of miR-101 has been reported to associate with upregulation of EZH2 in bladder and prostate cancers [126]. ATL cells show decreased levels of miR101 expression compared to cells from HTLV-1 carriers, the phenomenon that is not caused by genomic loss of miR-101 gene, while, in contrast such a decrease is caused by genomic loss of the miR-101 gene in prostate cancer [80]. Decreased expression of miR101 promotes overexpression of EZH2, offering miR-101 as a negative regulator of EZH2 in ATL cells. In that study miR-128a showed clearly the same pattern like miR-101, as underexpression of miR-128a also correlated with increased expression of EZH2 in ATL [80]. Sequencing of 3′-UTR of EZH2 mRNA revealed two predicted binding site for miR-101 and one for miR-26a [127]. By same analyzes it has been found that there is also one target site for miR-128a near the miR-101 target sites [80]. Nevertheless, miR-26a was shown with no decrease in ATL cells and no correlation was observed between miR-26a and EZH2 expression [80]. However, in normal physiological conditions miR-26a was associated with EZH2 in cell differentiation [80]. More recently Correia et al. reported that miR-101 is decreased in T-ALL patient and T-ALL cell lines and may be implicated in pathology of acute T-lymphoblastic leukemia [128] that was further supported by Qian et al. [129].