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

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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.

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Acknowledgements

We thank all the members of Professor Ah-Ng Kong’s laboratory for their invaluable discussion and technical support for preparation of this manuscript.

Funding

This work was supported in part by institutional funds and by R01 AT009152 from the National Center for Complementary and Integrative Health (NCCIH), R01 CA200129 from the National Cancer Institute (NCI), and P30 ES005022 from the National Institute of Environmental Health (NIEHS).

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Authors and Affiliations

  1. Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA

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

  2. Graduate Program of Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, USA

    Lujing Wang, Davit Sargsyan, Hsiao-Chen Kuo & Pochung Chou

  3. Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, 08903, USA

    Yujue Wang & Xiaoyang Su

  4. Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey, 08903, USA

    Yujue Wang & Xiaoyang Su

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  1. Lujing Wang
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Contributions

Participated in overall research study design: Lujing Wang and Ah-Ng Kong

Conducted experiments: Lujing Wang, Ameya Phadnis, and Shan Su

Performed data analysis: Lujing Wang, Renyi Wu, Davit Sargsyan, Shanyi Li, Hsiao-Chen Kuo, Pochung Chou, Yujue Wang, and Xiaoyang Su

Wrote the manuscript: Lujing Wang, Md Shahid Sarwar, and Ah-Ng Kong

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Correspondence to Ah-Ng Kong.

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Supplementary Information

ESM 1

Nfe2l2 KDmediated metabolites and metabolism pathway regulation in JB6 cells. Top 50 modulated metabolites with their corresponding P-value after Nfe2l2 KD are presented in Tab 1; the pathway analysis produced the significantly regulated metabolism pathways after Nfe2l2 KD are presented in Tab 2; and the pathway enrichment analysis produced significantly regulated pathways after Nfe2l2 KD are presented in Tab 3. (XLSX 13 kb)

ESM 2

DMRs and DEGs which are negatively regulated by TPA and FX. Tab 1: DMRs which are negatively regulated in TPA vs Control and TPA+FX vs TPA comparison groups; Tab 2: DEGs which are negatively regulated in TPA vs Control and TPA+FX vs TPA comparison groups. (XLSX 18 kb)

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Correlated genes which possess negatively DNA methylation and gene expression patterns in TPA vs Control and TPA+FX vs TPA comparison groups filtered by integration of RNA-seq and Methyl-seq Analysis (XLSX 12 kb)

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(DOCX 15 kb)

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Wang, L., Wu, R., Sargsyan, D. et al. Nfe2l2 Regulates Metabolic Rewiring and Epigenetic Reprogramming in Mediating Cancer Protective Effect by Fucoxanthin. AAPS J 24, 30 (2022). https://doi.org/10.1208/s12248-022-00679-0

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  • DOI: https://doi.org/10.1208/s12248-022-00679-0

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