Sulforaphane (SFN), an isothiocyanate in cruciferous vegetables including broccoli, cabbage, cauliflower, Chinese cabbage, and watercress, has strong anti-cancer/cancer chemopreventive potentials. Transcription factor nuclear factor erythroid 2 p45 (NF-E2)-related factor 2 (Nrf2) plays an important role in regulating the expressions of cellular antioxidant and detoxification enzymes. In this study, we investigated the preventive effect of SFN on tumor promoter-induced transformation in mouse skin epidermal JB6 promotion-sensitive (JB6 P+) cells, which might be involved with the activation of Nrf2. After 5 days pre-treatment, the results showed that SFN significantly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation. SFN enhanced nuclear translocation of Nrf2 and increased the Nrf2 downstream target enzymes including HO-1, NQO1, and UGT1A1 at both the transcriptional and protein levels. Comparing to shMock-transfected cells, TPA effectively induced colony formation in shNrf2 knockdown transfected cells were more resistant to the inhibitory effects of SFN. SFN's induction of Nrf2, HO1, and NQO1 protein expressions in shNrf2-transfected cells were lower than those in shMock-transfected cells. Epigenetics study showed that SFN suppresses methyltion ratio of the first fifteen CpGs in the promoter of Nrf2 gene in JB6 P+ cells utilizing bisulfite sequencing. Furthermore, SFN strongly reduced the protein expressions of DNA methyl transferases (DNMTs) including DNMT1, DNMT3a, and DNMT3b. In terms of histone deacetylases (HDACs), SFN not only inhibited total HDAC activity but also decreased the protein levels of HDAC1, HDAC2, HDAC3, and HDAC4, significantly. Taken together, these findings suggest that epigenetic re-activation of Nrf2 with subsequent induction of Nrf2 downstream target genes by SFN may provide insights into the chemopreventive mechanism of SFN against tumor promoter-induced mouse skin carcinogenesis.

Citation Format: Zheng-Yuan Su, Limin Shu, Chengyue Zhang, Tin Oo Khor, Jong Hun Lee, Tien-Yuan Wu, Allan H. Conney, Ah-Ng Tony Kong. Sulforaphane suppresses 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse epidermal JB6 P+ cell transformation through epigenetic re-activation of Nrf2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3658. doi:10.1158/1538-7445.AM2013-3658

©2013 American Association for Cancer Research
2013