Technical Abstract: Epigenetic silencing of tumor suppressors and pro-apoptosis genes in cancer cells, unlike genetic mutations, can potentially be reversed by the use of DNA demethylating agents (to remove methylation marks on the DNA) and HDAC inhibitors (to increase histone acetylation). It is now well established that plant-based foods are a natural source of modifiers of the epigenetic machinery. We believe that the ability of lunasin to upregulate expression of chemopreventive genes is associated with, and possibly due to, a lunasin-dependent increase in H4K16 acetylation in non-tumorigenic RWPE1 cells. Furthermore, the inability of lunasin to upregulate chemopreventive genes in tumorigenic RWPE2 cell line suggests that epigenetic changes (i.e., histone hypoacetylation coupled with DNA hypermethylation) within the promoters of these genes may have occurred during the course of Ki-ras oncogenic transformation of RWPE1 into RWPE2. As a dietary peptide capable of upregulation of chemopreventive gene expression by specific epigenetic modifications of the human genome, we believe the lunasin represents a novel regulatory motif and another food bioactive with the potential to reduce cancer risk. This could explain the long-standing inverse correlation between increased soy consumption and risk of various cancers. Future studies will be directed toward investigating the synergistic affects of lunasin in therapeutic combination with other natural chromatin remodeling bioactive agents.