Inhibition of Core Histone Acetylation by the Cancer Preventive Peptide Lunasin

Abstract

Lunasin is a unique 43 amino acid soy peptide that has been shown to be chemopreventive in mammalian cells and in a skin cancer mouse model in this work against oncogenes and chemical carcinogens. The observation that lunasin inhibits core histone acetylation led to the proposal of an epigenetic mechanism by which lunasin selectively kills cells that are being transformed by disrupting the dynamics of cellular histone acetylation-deacetylation when the transformation event is triggered by the inactivation of tumor suppressors that function via histone deacetylation. Here is reported for the first time the core histone H3- and H4-acetylation inhibitory properties of lunasin from different Korean soybean varieties used for various food purposes and from tissues of rats fed with lunasin-enriched soy (LES) to measure bioavailability. Lunasin was analyzed by immunostaining and inhibition of core histone acetylation by a non-radioactive histone acetyl transferase assay. Various amounts of lunasin are found in the soybean varieties, which correlated with the extent of inhibition of core histone acetylation. Both soy lunasin and synthetic lunasin inhibit core histone acetylation in a dose-dependent manner. Lunasin in LES is protected from in vitro digestion by pepsin. Lunasin extracted from blood and liver of rats fed with LES is intact and inhibits core histone acetylation.

The soybean peptide lunasin promotes apoptosis of mammary epithelial cells via induction of tumor suppressor PTEN: similarities and distinct actions from soy isoflavone genistein

“…These findings are consistent with previous reports showing that LUN stimulated apoptosis in human colon and breast cancer cells Hsieh et al 2010a) but had no effect on the growth of numerous immortalized and established cancer lines (Lam et al 2003). Our findings that sera from SPI-fed rats significantly influenced PTEN expression, PTEN nuclear localization, and cellular apoptosis, relative to sera from control diet (CAS)-fed mice are consistent with studies reporting the presence of bioactive components such as the isoflavones genistein and daidzein, and LUN in human and rodent sera after dietary soy protein intake (Jeong et al 2007;Jeong et al 2010;Dia et al 2009). Based on the reported LUN concentrations of 14 nM in plasma of men after soy consumption (Dia et al 2009) and the potential for degradation of LUN when dissociated from its complex with the Bowman-Birk protease inhibitor (Hsieh et al 2010a), the latter a component of soy proteins, we used LUN at higher concentration (50 nM and 1-2 lM) for evaluating its effects on mammary epithelial cells, since these cells were not co-treated with the protease inhibitor.…”

“…To evaluate the possibility that the soy peptide Lunasin (LUN) exerts mammary tumor-inhibitory activities by influencing PTEN expression similar to GEN, MCF-7 cells treated with LUN were evaluated for effects on PTEN transcript and promoter activity, PTEN protein levels, and PTEN nuclear localization, relative to cells treated with vehicle and in some cases, GEN. For these studies, synthetic LUN was used at concentrations (50 nM or 2 lM) higher than its range of detection in sera of humans and rodents exposed to dietary soy (Jeong et al 2007;Dia et al 2009), since LUN is readily degraded in the absence of Bowman-Birk protease inhibitor (Hsieh et al 2010c), and this inhibitor was not included in the culture medium. Synthetic LUN and LUN purified from soybeans were previously demonstrated to exhibit similar bioactivities in L2110 leukemia cells (De Mejia et al 2010).…”

“…Lunasin (LUN) is a 43-amino acid peptide component of post-translationally processed 2S albumin, initially identified in soybeans (Galvez and de Lumen 1999) and also present in barley, wheat and other seeds (Jeong et al 2007(Jeong et al , 2010Silva-Sanchez et al 2008). The anti-carcinogenic properties of LUN have been demonstrated in rodent models of skin (Galvez et al 2001) and breast (Hsieh et al 2010a, b) cancers and in colon and breast cancer cell lines Hsieh et al 2010c;Dia and Gonzalez de Mejia 2011).…”

Lunasin: A promising polypeptide for the prevention and treatment of cancer

“…However, the inhibitory activity of histone acetylation was also markedly associated with the concentration of lunasin. Lunasin at a concentration of 10 nmol/l was able to decrease the acetylation of histones by between 20 and 25%; by contrast, lunasin at a concentration <1 µmol/l was able to decrease the acetylation of histones H3 and H4 by 80 and 74%, respectively (50). Lunasin was able to act on cells at the stage of division or transformation, which is described by the E1A-Rb-histone deacetylase (HDAC) model (Fig.…”

1997-2012: Fifteen Years of Research on Peptide Lunasin

“…Its sequence is SKWQHQQDSCRKQLQGVNLTPCEKHIMEKIQGRGDDDDD DDDD, containing 9 Asp residues, and an Arg-Gly-Asp cell adhesion motif [15]. Lunasin was first identified in the soybean seed, with variable concentrations ranged from 0.5 to 8.1 mg lunasin/g seed [16,17]. This variation has been found to mainly depend on the soybean genotype, suggesting the possibility of selecting and breeding varieties of soybean with higher lunasin contents [16].…”