Histone methyltransferases as a new target for the epigenetic action by vorinostat

Abstract

Aberrant methylation and acetylation of histones are characteristic changes in the system of epigenetic regulation of gene expression accompanying the process of malignant transformation of the cell. Vorinostat is the epigenetic modulator that actively used in clinical oncology practice. The antitumor activity of vorinostat is considered to be associated with only with the inhibition of histone deacetylases. The effects of this drug on histone methylation have not been sufficiently studied. Using the HeLa TI test system, which allows evaluating the integral effect of epigenetically active compounds by activating the expression of the reporter gene GFP, and knockdown of genes by small interfering RNAs, we showed that the inhibitory effect of vorinostat is directed not only at HDAC1, but also at EZH2, SUV39H1, SUV39H2, SUV420H1. Using Western blotting, the ability of vorinostat to suppress the expression of enzymes EZH2, SUV39H1/2, SUV420H1 was confirmed and, in addition, its ability to inhibit the expression of enzymes SUV420H2 and DOT1L was revealed. The data obtained expand the understanding of the epigenetic effects of vorinostat and demonstrate the need for a large-scale analysis of its activity in relation to other epigenetic enzymes. A detailed understanding of the mechanism of epigenetic action of vorinostat will contribute to its more adequate use in the treatment of tumors with an aberrant epigenetic profile.