Abstract
Sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables, induces potent anti-proliferative effects in prostate cancer cells. One mechanism that may contribute to the anti-proliferative effects of SFN is the modulation of epigenetic marks, such as inhibition of histone deacetylase (HDAC) enzymes. However, the effects of SFN on other common epigenetic marks such as DNA methylation are understudied. Promoter hyper-methylation of cyclin D2, a major regulator of cell cycle, is correlated with prostate cancer progression, and restoration of cyclin D2 expression exerts anti-proliferative effects on LnCap prostate cancer cells. Our study aimed to investigate the effects of SFN on DNA methylation status of cyclin D2 promoter, and how alteration in promoter methylation impacts cyclin D2 gene expression in LnCap cells. We found that SFN significantly decreased the expression of DNA methyltransferases (DNMTs), especially DNMT1 and DNMT3b. Furthermore, SFN significantly decreased methylation in cyclin D2 promoter regions containing c-Myc and multiple Sp1 binding sites. Reduced methlyation of cyclin D2 promoter corresponded to an increase in cyclin D2 transcript levels, suggesting that SFN may de-repress methylation-silenced cyclin D2 by impacting epigenetic pathways. Our results demonstrated the ability of SFN to epigenetically modulate cyclin D2 expression, and provide novel insights into the mechanisms by which SFN may regulate gene expression as a prostate cancer chemopreventive agent.
Highlights
Studies have shown that high consumption of cruciferous vegetables is inversely associated with prostate cancer risk [1,2,3,4,5]
Our results indicate that SFN may down-regulate DNA methyltransferases (DNMTs) resulting in de-methylation of the cyclin D2 promoter and de-repression of cyclin D2 expression, and suggest a novel mechanism behind SFN’s growth inhibitory effects on prostate cancer cells
Sulforaphane decreased DNA methyltransferase expression We assessed the effects of SFN on the expressions of DNMTs (DNMT1, DNMT3a, and DNMT3b) in benign hyperplasia (BPH-1), LnCap and PC3 prostate cancer cells
Summary
Studies have shown that high consumption of cruciferous vegetables is inversely associated with prostate cancer risk [1,2,3,4,5]. Cruciferous vegetables and their biologically active constituents, including isothiocyanates (ITCs) such as sulforaphane (SFN), appear to modulate prostate cancer risk at multiple stages of carcinogenesis. SFN is an effective chemoprotective agent for prostate cancer in both in vitro and in vivo models by selectively inducing apoptosis and slowing tumor growth [6,7,8,9,10]. SFN has been shown to induce anti-proliferative effects via epigenetics, namely acting as a dietary histone deacetylase (HDAC) inhibitor.
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