Abstract A62: Increased histone acetylation, but no inhibition of HDAC activity, by kale sprout intervention in a human prostate cancer xenograft model

Abstract

Abstract Cruciferous vegetable consumption has been associated with a reduced risk of prostate cancer. These vegetables such as broccoli and kale are rich in glucosinolates, which are converted to isothiocyanates (ITCs) by myrosinase. ITCs have cancer preventive potential through various mechanisms including anti-proliferative effects. ITC metabolites have been recently identified as inhibitors of histone deacetylases (HDAC), which have the potential to turn on epigenetically silenced genes, leading to cell cycle arrest and apoptosis. In the present study we investigated the effect of kale sprouts commercially available as a food supplement to inhibit the growth of human LNCaP prostate cancer cells in a xenograft model. We were interested whether kale sprout intervention would affect histone acetylation and in studying underlining mechanisms, e.g. HDACs and histone acetyltransferases (HAT). LNCaP human prostate cancer cells were injected to male nude Balb/c mice (10 per group). Mice were fed with either regular rodent chow or chow supplemented with 20% kale sprouts (containing about 60 µmol glucosinolates per 5 g chow consumed daily, together with active myrosinase) from a week before cell injection until sacrifice. 7.5 weeks after injection, tumor tissue was collected. Kale sprout intervention did not significantly inhibit tumor growth in the xenograft model. However, global acetylation levels of histone H4 detected by Western blotting were increased in the kale sprout-treated group, whereas acetylated histone H3 levels were not significantly changed. The increase of H4 lysine 5, 8, 12 and 16 acetylation was individually confirmed. Among them, acetylated H4 K12 was most abundant. Even though global acetylation of H3 did not change, acetylated H3K9 was significantly increased. Unexpectedly, HDAC activity in nuclear extracts of tumor tissue determined by using ZMAL substrate was not significantly inhibited in tumor tissue by kale sprout intervention. Also, protein expression of HDAC family members HDAC1-5 was not changed overall, although HDAC 5 expression was reduced while HDAC2 expression was increased. Instead, kale sprout treatment significantly increased mRNA levels of PCAF and CBP quantified by qRT-PCR, by 36% and 23%, respectively, in tumor tissue (p<0.001), which may contribute to increased H4 acetylation. Taken together, our results indicate that dietary consumption of kale sprouts increased global acetylation of histone H4 in LNCaP prostate cancer xenograft model, possibly by induction of HAT expression rather than inhibition of HDAC activity. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A62.