Lunasin is a unique 43-amino acid soybean peptide that contains at its carboxyl end: (a) nine Asp (D) residues; (b) an Arg-Gly-Asp (RGD) cell adhesion motif; and (c) a predicted helix with structural homology to a conserved region of chromatin-binding proteins. We demonstrated previously that transfection of mammalian cells with the lunasin gene arrests mitosis, leading to cell death. Here we show that exogenous application of the lunasin peptide inhibits chemical carcinogen-induced transformation of murine fibroblast cells to cancerous foci. To elucidate its mechanism of action we show that lunasin: (a) internalizes in the cell through the RGD cell adhesion motif; (b) colocalizes with hypoacetylated chromatin; (c) binds preferentially to deacetylated histone H4 in vitro; and (d) inhibits histone H3 and H4 acetylation in vivo in the presence of a histone deacetylase inhibitor. These results suggest a mechanism whereby lunasin selectively induces apoptosis, mostly in cells undergoing transformation, by preventing histone acetylation. In support of this, lunasin selectively induces apoptosis in E1A-transfected cells but not in nontransformed cells. Finally, in the SENCAR mouse skin cancer model, dermal application of lunasin (250 microg/week) reduces skin tumor incidence by approximately 70%, decreases tumor yield/mouse, and delays the appearance of tumors by 2 weeks relative to the positive control. These results point to the role of lunasin as a new chemopreventive agent that functions possibly via a chromatin modification mechanism.