No abstract

A novel epigenetic modulator that displays a DNMT1 inhibition and DNMT3A activation profile was characterized (compound 8). This compound is a derivative of palmitic acid that incorporates the putative reactive functional group (diynone) of the peyssonenyne natural products. Other analogues containing the diynone or an acetoxyenediyne did not show the same biological profile. In U937 human leukemia cells, diynone 8 induced cell differentiation and apoptosis, which correlated with the expression of Fas protein. Very surprisingly, diynone 8 was toxic to normal human fibroblasts (BJ) and mouse embryo fibroblasts (MEF), but not to immortalized human fibroblasts (BJEL); this unique effect was not observed with the classical DNMT inhibitor 5-azacytidine. Therefore, compound 8 interferes in a very specific manner with signaling pathways, the activities of which differ between normal and immortalized cell types. This toxicity is reminiscent of the effects of Dnmt1 ablation on mouse fibroblasts. In fact, some of the genes deregulated by the loss of Dnmt1 are similarly deregulated by 8, but not by the DNMT inhibitor SGI-1027.

The front cover picture shows a knight that represents a derivative of the natural product peyssonenyne, a novel DNA methyl transferase (DNMT) epigenetic modulator, armed with a reactive diynone weapon. This chemical warrior was found to be toxic to normal human fibroblasts (BJ, left maze) and mouse embryo fibroblasts (MEF), but not to immortalized human fibroblasts (BJEL, right maze), a unique effect not observed with the classical DNMT inhibitor azacytidine. Based on this toxicity for normal cells, short‐term or local application of this epigenetic modulator holds potential for therapy of diseases based on hyperproliferation of fibroblasts or other (pathological) scarring diseases. For more details, see the Full Paper by Lucia Altucci, Hinrich Gronemeyer, Ángel R. de Lera et al. on . Illustration created by Alex Pelayo.