**4. Epigenetic alterations in chromosomal DNAs and proteins**

Epigenetic alterations are frequently found in cancer, implying that "cancer is an epigenetic disease" [96]. It has been hypothesized that epigenetic and/or transcriptional changes play a role in determining the chromatin state in tumor cells [97]. Epigenetic regulation is mainly driven by modifications of chromosomal DNAs and histone proteins [98]. The biological relevance between cellular metabolites and the gene expression has been proposed as the RNA/enzyme/metabolite (REM) networking system [99]. The metabolites, NAD+ , S-adenosylmethionine (AdoMet), and acetyl-CoA, are the substrates for poly (ADP-ribosyl) ation, methylation, and acetylation, respectively [76], suggesting that these metabolic statedependent molecules play important roles in the epigenetic regulation.
