Jumonji domain-containing lysine demethylase (KDM) enzymes are encoded by genes of the KDM superfamily. Activities of the KDM4 subfamily promote aggressive phenotypes associated with prostate cancer (PCa). Previously, we discovered a benzimidazole pyrazole molecule that inhibited KDM4 isoforms with properties tractable for development. Here, we demonstrate that a benzyl-substituted variant of this inhibitor exhibits improved potency in biochemical assays, is cell-permeable, and kills PCa cells at low micromolar concentrations. By X-ray crystallography and kinetics-based assays, we demonstrate that the mechanism of inhibition is complex, proceeding via competition with the enzyme for binding of active-site Fe2+ and by populating a distal site on the enzyme surface. Furthermore, we provide evidence that the inhibitor’s cytostatic properties arise from direct intracellular inhibition of KDM4 enzymes. PCa cells treated with the inhibitor exhibit reduced expression of genes regulated by the androgen receptor, an outcome accompanied by epigenetic maintenance of a heterochromatic state.

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The objective of the study was to investigate possible effect of the polymorphism in pigeon α A-globin (AGLOB) gene on its expression level. The g.5768C>T substitution located in 3 flanking region of the gene was analyzed. PCR-RFLP (AvaII) method was used to identify the SNP. The gene expression analyses were performed using qPCR. The investigation indicated a difference but not significant in the α A-globin gene expression levels between pigeons carrying different g.5768C>T genotypes. The AGLOB CC genotype was associated with 2.46-fold higher expression level of pigeon α A-globin gene compared to AGLOB TT genotype. The lower expression of α A-globin gene in AGLOB TT pigeons may be caused by the presence of cis-acting regulatory elements in the analysed gene region.