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  • In conclusion we have demonstrated that the

    2021-09-15

    In conclusion, we have demonstrated that the ejection of structural zinc ions from G9a and GLP in the presence of selenium-, and sulfur-containing electrophilic small Exo1 leads to inhibition of these two biomedically important epigenetic enzymes. Our work demonstrates that clinically used ebselen, disulfiram and cisplatin act as very effective inhibitors of G9a and GLP with submicromolar or low micromolar IC values. It is possible that the observed physiological effects of these molecules may in part arise as a result of their ability to affect epigenetic processes regulated by G9a and GLP methyltransferases. Inhibition of biomedically important epigenetic processes is currently a subject of intensive investigations, therefore we envision that future studies will lead to important advances in design and development of specific inhibitors of the therapeutic potential. Although it is unlikely that highly electrophilic compounds studied here, most notably ebselen, act as specific inhibitors of endogeneous proteins, it might be possible that exploring a broader chemical space via substitutions on the ebselen and disulfiram scaffolds may lead to a higher degree of specificity for certain protein targets. Detailed structure-activity relationships studies on small molecules that target structural zinc fingers may direct a design of novel type of inhibitors with an improved selectivity. Towards this aim, our work highlights that targeting zinc finger sites of histone lysine methyltransferases is an alternative strategy to commonly used approaches that target histone substrate and SAM cosubstrate binding sites; this strategy leads to efficient inhibition of G9a and GLP histone lysine methyltransferases that possess structural zinc ions. Acknowledgments We thank the Netherlands Organization for Scientific Research (NWO, NCI-TA grant 731.015.202) for funding.
    Introduction Overexpression of the enhancer of zeste homologue 2 (EZH2) gene has been associated with tumourigenicity in numerous solid tumour types [1], [2], [3], [4], [5], [6], [7], and gain-of-function point mutations in the catalytically active SET domain of EZH2 has been recognized in B-cell and T-cell lymphomas [8], [9], [10], [11], [12], [13], [14], [15], [16]. Genetic loss-of-function studies have demonstrated a crucial role of EZH2 in the establishment of cell fate decisions in the skin, heart and Exo1 mammary glands [17]. EZH2 together with suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED) forms part of the Polycomb repressive complex 2 (PRC2), which mediates the silencing of genes by trimethylation of lysine 27 on histone H3 (H3K27me3) [18], [19]. This H3k27me3 mark has been found in genes that play a key role in cellular processes such as cell differentiation, cell cycle regulation and oncogenesis [20], [21], [22]. However, recent studies suggest that EZH2 directly binds to the promoter regions of certain genes and acts as a transcriptional co-activator independent of its histone methyltransferase enzymatic activity [23], [24], [25]. Neuroblastoma is a neuroendocrine tumour that arises from the peripheral nervous system [26]. It is the most commonly diagnosed extracranial solid cancer in children, accounting for approximately 15% of all pediatric cancer deaths [27], [28]. Chromosome 17q gain, partial loss of chromosome 1p or 11q and v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) amplification are frequently observed genetic aberrations in neuroblastoma tumours [29]. EZH2 is located on chromosome 7q35, and frequent gains of whole chromosome 7 have been observed in neuroblastoma [30], [31]. A functional role for EZH2 in neuroblastoma was reported, whereas EZH2 caused histone hypermethylation in the promoter regions of known tumour suppressor genes CASZ1, CLU, RUNX3 and NGFR resulting in the silencing and downregulation of these genes [32]. In the present study, we show that pharmacological inhibition of EZH2 histone methyltransferase activity [33], [34], [35], [36] only causes limited inhibitory effects on cell cycle progression, whereas silencing of the whole protein causes a strong apoptotic phenotype. We overcame apoptosis caused by EZH2 silencing by overexpressing a truncated form of wild-type EZH2 lacking histone methyltransferase activity. These findings highlight the importance of EZH2 for the survival of neuroblastoma cells independent of its histone methyltransferase activity and development of compounds that inhibit EZH2 protein as a whole might be beneficial for the treatment of neuroblastoma patients with high EZH2 expression.