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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Nfe2l2 Regulates Metabolic Rewiring and Epigenetic Reprogramming in Mediating Cancer Protective Effect by Fucoxanthin.

Authors: Wang, Lujing; Wu, Renyi; Sargsyan, Davit; Su, Shan; Kuo, Hsiao-Chen; Li, Shanyi; Chou, Pochung; Sarwar, Md Shahid; Phadnis, Ameya; Wang, Yujue; Su, Xiaoyang; Kong, Ah-Ng

Published In AAPS J, (2022 Jan 18)

Abstract: Fucoxanthin (FX) is a carotenoid with many pharmaceutical properties due to its antioxidant/anti-inflammatory and epigenetic effects. NFE2L2 is involved in the defense against oxidative stress/inflammation-mediated diseases, like anticancer effects elicited by phytochemicals including FX. However, the role of FX and NFE2L2 in metabolic rewiring, epigenomic reprogramming, and transcriptomic network in blocking pro-tumorigenic signaling and eliciting cancer-protective effects remains unknown. Herein, we utilized multi-omics approaches to evaluate the role of NFE2L2 and the impact of FX on tumor promoter TPA-induced skin cell transformation. FX blocked TPA-induced ROS and oxidized GSSG/reduced GSH in Nfe2l2wild-type(WT) but not Nfe2l2-knockdown (KD) cells. Both Nfe2l2 KD and TPA altered cellular metabolisms and metabolites which are tightly coupled to epigenetic machinery. The suppressive effects of FX on TPA-enhancedSAM/SAH was abrogated by Nfe2l2 KD indicating Nfe2l2 plays a critical role in FX-mediated metabolic rewiring and its potential consequences on epigenetic reprogramming. Epigenomic CpG methyl-seq revealed that FX attenuated TPA-induced differentially methylated regions (DMRs) of Uhrf1 and Dnmt1 genes. Transcriptomic RNA-seq showed that FX abrogated TPA-induced differentially expressed genes (DEGs) of Nfe2l2-related genes Nqo1, Ho1, and Keap1. Associative analysis of DEGs and DMRs identified that the mRNA expressions of Uhrf1 and Dnmt1 were correlated with the promoter CpG methylation status. Chromatin immunoprecipitation assay showed that FX restored Uhrf1 expression by regulating H3K27Me3 enrichment in the promoter region. In this context, FX/Nfe2l2's redox signaling drives metabolic rewiring causing epigenetic and transcriptomic reprogramming potentially contributing to the protection of TPA-induced JB6 cellular transformation skin cancer model. Graphical abstract.

PubMed ID: 35043283 Exiting the NIEHS site

MeSH Terms: Animals; Antioxidants/pharmacology; Cell Line; Cell Transformation, Neoplastic/drug effects; Epigenesis, Genetic*; Gene Expression Regulation/drug effects; Gene Knockdown Techniques; Mice; NF-E2-Related Factor 2/genetics*; Oxidation-Reduction/drug effects; Reactive Oxygen Species/metabolism; Signal Transduction/drug effects; Skin Neoplasms/genetics; Skin Neoplasms/pathology; Skin Neoplasms/prevention & control*; Tetradecanoylphorbol Acetate; Xanthophylls/pharmacology*

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