Anthocyanin Delphinidin Prevents Neoplastic Transformation of Mouse Skin JB6 P+ Cells: Epigenetic Re-activation of Nrf2-ARE Pathway

Abstract

Redox imbalance is a major contributor to the pathogenesis of melanoma and nonmelanoma skin cancer. Activation of the nuclear factor E2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) pathway is an intrinsic defense mechanism against oxidative stress. Flavonoids such as anthocyanidins, which are found abundantly in fruits and vegetables, have been shown to activate Nrf2. However, the epigenetic and genetic mechanisms by which anthocyanidins modulate the Nrf2-ARE pathway remain poorly understood in the context of skin cancer. In this study, delphinidin, one of the most potent and abundant anthocyanidins in berries, significantly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic cell transformation in mouse epidermal JB6 P+ cells by 69.4% to 99.4%. The mechanism was elucidated based on observations of increased ARE-driven luciferase activity and elevated mRNA and protein expression of Nrf2 downstream genes, such as heme oxygenase-1 (Ho-1), in JB6 P+ cells. Activation of the Nrf2-ARE pathway was correlated with demethylation of 15 CpG sites in the mouse Nrf2 promoter region between nt −1226 and −863 from the transcription start site. The reduced CpG methylation ratio in the Nrf2 promoter region was consistent with observed decreases in the protein expression of DNA methyltransferases 1 (DNMT1), DNMT3a and class I/II histone deacetylases (HDACs). Overall, our results suggest that delphinidin, an epigenetic demethylating agent of the Nrf2 promoter, can activate the Nrf2-ARE pathway, which can be applied as a potential skin cancer chemopreventive agent.

Maqui berry extract prevents cigarette smoke induced oxidative stress in human osteoblasts in vitro

“…However, hOBs exposed to MBE were not observed to activate ROS or nitrotyrosine production, suggesting MBE, as an antioxidant, can activate the expression of Nrf2. This result is consistent with another study which showed that delphinidin can activate Nrf2 as an epigenetic demethylating agent of the Nrf2 promoter (Kuo et al, 2019[ 24 ]). We exposed MBE and CSE to hOBs in three incubation modes including pre-incubation, co-incubation and post-incubation as described.…”

Inhibitory Effect of Delphinidin on Oxidative Stress Induced by H2O2 in HepG2 Cells

“…They have an antioxidant activity which is associated with the diorthohydroxyl functional moiety. Among various kinds of anthocyanins, delphinidin (Dp) has attracted much attention due to its largest number of hydroxyl groups on the B ring and high antioxidant activity [ 30 , 31 ]. In this study, the HepG2 cells, which possessed many biological characteristics of hepatocytes and the activity of many phases I and II antioxidant enzymes, were selected to evaluate the antioxidative property effect of delphinidin treatment [ 32 , 33 ].…”

“…In fact, that is because heme-derived metabolites produced by HO-1 have powerful antioxidant and cytoprotective activities [ 46 , 47 ]. In addition, according to the related researches, it has been found that HO-1 and NQO1 could be effectively activated by Nrf2 [ 30 ]. In our study, delphinidin treatment significantly upregulated the protein expression of Nrf2 and HO-1 ( Figure 3 ).…”

Epigenetic Regulation of NRF2/KEAP1 by Phytochemicals

“…The anthocyanidin decreased the CpG methylation ratio at the Nfe2l2 promoter resulting in upregulated mRNA and protein expression levels of Nrf2 and its target genes. The study further demonstrated downregulation of Dnmts (Dnmt1a and Dnmt3a), and class I and II Hdacs linked to reactivation of the Nrf2 pathway in JB6 P+ cells [84].…”