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Taxifolin Activates the Nrf2 Anti-Oxidative Stress Pathway in Mouse Skin Epidermal JB6 P+ Cells through Epigenetic Modifications

Key Laboratory of Chinese Materia Medica, Heilongjiang University of Chinese Medicine, Harbin 150040, China
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
College of Pharmacy, Harbin Medical University, Harbin 150086, China
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(7), 1546;
Received: 26 May 2017 / Revised: 4 July 2017 / Accepted: 7 July 2017 / Published: 17 July 2017
(This article belongs to the Special Issue Cancer Epigenetics)
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Nuclear factor erythroid-2 related factor 2 (Nrf2) is a vital transcription factor that regulates the anti-oxidative defense system. Previous reports suggested that the expression of the Nrf2 gene can be regulated by epigenetic modifications. The potential epigenetic effect of taxifolin (TAX), a potent cancer chemopreventive agent, in skin cancer chemoprotection is unknown. In this study, we investigated how Nrf2 is epigenetically regulated by TAX in JB6 P+ cells. TAX was found to inhibit the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced colony formation of JB6 P+ cells. TAX induced antioxidant response element (ARE)-luciferase activity in HepG2-C8 cells and up-regulated mRNA and protein levels of Nrf2 and its downstream genes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1), in JB6 P+ cells. Furthermore, bisulfite genomic sequencing revealed that TAX treatment reduces the methylation level of the first 15 CpGs sites in the Nrf2 promoter. Western blotting showed that TAX inhibits the expression levels of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) proteins. In summary, our results revealed that TAX can induce expression of Nrf2 and its downstream target genes in JB6 P+ cells by CpG demethylation. These finding suggest that TAX may exhibit a skin cancer preventive effect by activating Nrf2 via an epigenetic pathway. View Full-Text
Keywords: skin cancer; Nrf2; epigenetics; taxifolin; JB6 P+ cells skin cancer; Nrf2; epigenetics; taxifolin; JB6 P+ cells

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Kuang, H.; Tang, Z.; Zhang, C.; Wang, Z.; Li, W.; Yang, C.; Wang, Q.; Yang, B.; Kong, A.-N. Taxifolin Activates the Nrf2 Anti-Oxidative Stress Pathway in Mouse Skin Epidermal JB6 P+ Cells through Epigenetic Modifications. Int. J. Mol. Sci. 2017, 18, 1546.

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