title: A γ-tocopherol-rich mixture of tocopherols maintains Nrf2 expression in prostate tumors of TRAMP mice via epigenetic inhibition of CpG methylation.
abstract: Nuclear factor-erythroid 2-related factor 2 (Nrf2) plays a pivotal role in maintaining cellular redox homeostasis and eliminating reactive toxic species. Nrf2 is epigenetically suppressed due to CpG hypermethylation in prostate tumors from the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. We previously showed that dietary feeding of a γ-tocopherol-rich mixture of tocopherols (γ-TmT) suppressed prostate tumorigenesis in TRAMP mice associated with higher Nrf2 protein expression. We hypothesized that γ-TmT may maintain Nrf2 through epigenetic inhibition of promoter CpG methylation. In this study, 8-wk-old male TRAMP mice were fed 0.1% γ-TmT or a control diet for 16 wk. The methylation in the Nrf2 promoter was inhibited in the prostate of the γ-TmT group compared with the control group. Protein expressions of DNA methyltransferase (DNMT), including DNMT1, DNMT3A, and DNMT3B, were lower in the prostate of the γ-TmT group than in the controls. TRAMP-C1 cells were treated with 30 μmol/L of γ-TmT or blank medium for 5 d. The methylation in the Nrf2 promoter was inhibited in the γ-TmT-treated cells compared with the untreated cells at d 5, and mRNA and protein expressions of Nrf2 and NAD(P)H:quinone oxidoreductase 1 were higher. Interestingly, only DNMT3B was inhibited in the γ-TmT-treated cells compared with the untreated cells. In the aggregate, our findings demonstrate that γ-TmT could inhibit CpG methylation in the Nrf2 promoter in the prostate of TRAMP mice and in TRAMP-C1 cells, which might lead to higher Nrf2 expression and potentially contribute to the prevention of prostate tumorigenesis in this TRAMP model.
authors.affiliation: Department of Pharmaceutics, Center for Cancer Prevention Research, Earnest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Tin Oo
authors.initials: TO
authors.lastname: Khor
authors.forename: Limin
authors.initials: L
authors.lastname: Shu
authors.forename: Constance Lay-Lay
authors.initials: CL
authors.lastname: Saw
authors.forename: Tien-Yuan
authors.initials: TY
authors.lastname: Wu
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D018899:CpG Islands / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics*; D024504:gamma-Tocopherol / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; D024504:gamma-Tocopherol; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse