Promoter de-methylation of cyclin D2 by sulforaphane in prostate cancer cells

Studies have shown that high consumption of cruciferous vegetables is inversely associated with prostate cancer risk [1-5]. 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 [6-10]. More recently, SFN has been shown to induce anti-proliferative effects via epigenetics, namely acting as a dietary histone deacetylase (HDAC) inhibitor. SFN treatment leads to an increase in histone acetylation and re-expression of various tumor suppressor genes [11-13]. SFN-mediated epigenetic alterations may not only be limited to HDAC regulation. Studies suggest that SFN may play an important role in methyl CpG-binding proteins' recruitment of HDAC family members [14]. In breast cancer cells, SFN suppresses DNA methylation in the hTERT promoter, leading to transcriptional repression [15]. Together, these data suggest that there may be multiple mechanisms by which SFN epigenetically regulates gene expressions.Cell cycle progression is controlled by cyclin-dependent kinases (CDKs) and their activities are further regulated by cyclins and CDK inhibitors. D-type cyclins (D1, D2, and D3) are mainly implicated in G1 to S phase transition [16]. Dys-regulation of the cyclin Ds disrupts cell cycle control and promotes neoplastic transformation. Cyclin D2/CCND2 has been identified in several cancers as a proto-oncogene. Over-expression of cyclin D2 correlates with progression and poor prognosis in gastric cancer [17,18], colon cancer [19] and granulosa cell tumors of the ovary [20]. However, silencing of cyclin D2 expression by promoter methylation is also associated with cancer progression in breast cancer [21-23], lung [23], pancreatic [24] and gastric cancer [25], suggesting that cycl