Modulating Epigenetic Modification Enzymes Through Relevant Epidrugs as a Timely Strategy in Anticancer Therapy

Abstract

Epigenetic mechanisms play a critical role in governing DNA-templated processes such as transcription. These mechanisms involve modifications on nucleosomal histones and the overlying DNA (Gibney and Nolan 2010). Though histone substrates undergo a variety of post-translational modifications, a single modification occurs to DNA (methylation at C-5 of cytosine). Modifications on histone proteins are primarily directed to unstructured N-terminal tails (Bannister and Kouzarides 2011; Kouzarides 2007). Among the histone modifications acetylation, ubiquitination, ADP-ribosylation, SUMOylation, methylation, phosphorylation and biotinylation are well known. DNA undergoes the only modification that is methylation (Bird 1992; Cao and Yan 2012; Robertson and Jones 2000; Verheugd et al. 2016). Certain modifications such as acetylation unanimously lead to transcriptional activation through chromatin remodelling by passive method (Grunstein 1997). The effect of histone methylation on gene expression depends on the site and degree of this epigenetic mark (Greer and Shi 2012). While histone H3K4me3 favours transcription, H3K9me3 and H3K27me3 have opposite effect (Barski et al. 2007). DNA methylation has silencing effect on gene expression (Kass et al. 1997; Siegfried et al. 1999). Transcriptional silencing due to DNA methylation may be either due to prevention of transcription factor binding or through recruitment of HDAC by way of and methyl-CpG-binding protein 2 (MECP2) (Curradi et al. 2002; Jones et al. 1998).