Abstract 2588: The effect of kava extracts and kavalactones on histone lysine methylation in urinary bladder cancer

According to the GLOBOCAN08, Cancer Incidence and Mortality Worldwide in 2008 report, age-standardized incidences of tobacco-smoking related lung and bladder cancers in three kava drinking pacific countries (Fiji, Vanutu and Samoa) were markedly lower than those in their neighbor countries, such as Australia and New Zealand, despite of the higher percentages of smokers in their populations (up to 58.3% of man in Samoa smoke). It has recently been thought that modification of reversible epigenetic events such as histone acetylation and methylation during carcinogenesis may be one of the most promising ways in prevention of tobacco-smoking related cancers. We therefore examined the effect of kava extracts and their main chemical components kavalactones on histone lysine methylation in malignant and non-malignant bladder cell lines. Our data have shown that the kava crude extract, kawain and methysticin but not dehydrokawain, yangonin, 11-methoxyyangonin in the extract induce expression of H3K4 me1 and me2, as well as H3K9 me2 in bladder cancer cell lines (5637, T24 and RT4). In addition, both kawain and methysticin significantly inhibits the in vitro activity of demethylase lysine-specific demethylase 1 (LSD1). Compared to non-malignant bladder epithelial cells TEU2, bladder cancer cells express very little or no H3K4 me1 and me2, as well as H3K9 me2. Among all the tested kavalactones, kawain demonstrated selectivity in inhibition of the growth of bladder cancer cells versus non-malignant bladder epithelial cells (TEU2). Consistent with the above results, a specific LSD1 inhibitor II and a nonspecific monoamine oxidases inhibitor trans-2-Phenylcyclopropylamine (2-PCPA, also known to inhibit LSD1) significantly induce the expression of H3K4 me1 and me2, as well H3K9me2 in tested bladder cancer cell lines. Furthermore, dietary feeding of 6 g kawain/kg mouse food significantly slows down hydroxybutyl(butyl)nitrosamine (OH-BBN)-induced mouse urinary bladder carcinogenesis and increases the survival rates of mice treated with OH-BBN in both prevention (kawain was given before the OH-BBN treatment) and promotion (kawain was given after the OH-BBN treatment) protocols. Immunohistochemistry on paraffin-embedded bladder sections revealed that OH-BBN-induced mouse bladder tumors show significantly decreased H3K4me1 expression (p=0.0005) compared to normal mouse bladders, whereas bladder tissues from kawain treated mice show a significant increase in the expression of H3K4me1 compared to those from vehicle control treated mice in the OH-BBN model (p=0.002). Taken together, our results suggested that modification of histone lysine methylation may represent a new approach for bladder cancer prevention and treatment, and that kavalacones may be promising cancer preventive agents existing in the kava plant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2588. doi:1538-7445.AM2012-2588