Abstract
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.
Highlights
Reactive oxygen species (ROS) are highly proactive molecules originating from free radicals and molecular oxygen [1]
The results showed that TAX treatments decreased cell viability in JB6 P+ cells and HepG2-C8 cells in a dose dependent manner (Figure 2A,B)
This study demonstrated that TAX might alter DNA demethylation and epigenetically enhance Nuclear factor erythroid-2 related factor 2 (Nrf2) expression, contributing to the prevention of the neoplastic growth of JB6 P+ cells
Summary
Reactive oxygen species (ROS) are highly proactive molecules originating from free radicals and molecular oxygen [1]. Oxidative stress is considered as the imbalance between pro-oxidants and anti-oxidants. Superfluous ROS production and impairment of cellular anti-oxidant defense system may cause endogenous oxidative stress [2]. ROS-induced oxidative stress has been implicated in the pathogenesis of carcinogenesis [3]. Skin cells are constantly exposed to ultra-violet (UV) radiation, carcinogens or mutagens, which could induce ROS generation in the skin. UV radiation is regarded as a major environmental factor in the development of skin carcinogenesis [4]. In the USA, skin cancer is highly common, and approximately one million new cases are diagnosed each year [7]. Research on skin cancer and development of new prophylactic agents require urgent attention
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