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Fucoxanthin Elicits Epigenetic Modifications, Nrf2 Activation and Blocking Transformation in Mouse Skin JB6 P+ Cells

  • Research Article
  • Theme: Natural Products Drug Discovery in Cancer Prevention
  • Published:
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Abstract

Nuclear factor erythroid-2-related factor-2 (Nrf2 or NFE2L2) is a master regulator of the anti-oxidative stress response, which is involved in the defense against many oxidative stress/inflammation-mediated diseases, including anticancer effects elicited by an increasing number of natural products. Our previous studies showed that the epigenetic modification of the Nrf2 gene plays a key role in restoring the expression of Nrf2. In this study, we aimed to investigate the epigenetic regulation of Nrf2 by astaxanthin (AST) and fucoxanthin (FX), carotenoids which are abundant in microalgae and seaweeds, in mouse skin epidermal JB6 P+ cells. FX induced the anti-oxidant response element (ARE)-luciferase and upregulated the mRNA and protein levels of Nrf2 and Nrf2 downstream genes in HepG2-C8 cells overexpressing the ARE-luciferase reporter. Both FX and AST decreased colony formation in 12-Otetradecanoylphorbol-13-acetate (TPA)-induced transformation of JB6 P+ cells. FX decreased the methylation of the Nrf2 promoter region in the JB6 P+ cells by the bisulfite conversion and pyrosequencing. Both FX and AST significantly reduced DNA methyltransferase (DNMT) activity but did not affect histone deacetylase (HDAC) activity in JB6 P+ cells. In summary, our results show that FX activates the Nrf2 signaling pathway, induces the epigenetic demethylation of CpG sites in Nrf2 and blocks the TPA-induced transformation of JB6 P+ cells, indicating the potential health-promoting effects of FX in skin cancer prevention.

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Abbreviations

ARE:

Anti-oxidant response element

AST:

Astaxanthin

5-aza:

5-aza-deoxycytidine

DNMT:

DNA methyltransferase

DNMT1:

DNA methyltransferase 1

DNMT3a:

DNA methyltransferase 3a

DNMT3b:

DNA methyltransferase 3b

DMSO:

Dimethyl sulfoxide

FBS:

Fetal bovine serum

FX:

Fucoxanthin

GCLC:

Glutamate-Cysteine Ligase, Catalytic Subunit

GSH:

Glutathione

GSS:

Glutathione synthetase

GST:

Glutathione-S-transferases

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HO-1:

Heme oxygenase-1

HDAC:

Histone deacetylases

NQO1:

NAD(P)H: quinone oxidoreductase 1

Nrf2:

Nuclear factor (erythroid-derived 2)-like 2, or NFE2L2

qRT–PCR:

Quantitative reverse-transcriptase polymerase chain reaction

ROS:

Reactive oxygen species; SEM, standard error of the mean

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ACKNOWLEDGEMENTS

We thank all members of Dr. Ah-Ng Kong’s lab for helpful discussions and preparation of this manuscript. This study was supported in part by R01 CA200129, R01-CA118947, and R01-CA152826 from the National Cancer Institute (NCI), R01 AT009152 from the National Center for Complementary and Integrative Health (NCCIH), and institutional funds awarded to Dr. Ah-Ng Kong.

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Authors and Affiliations

  1. Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, 08854, USA

    Yuqing Yang, Irene Yang, Mingnan Cao, Zheng-yuan Su, Renyi Wu, Yue Guo & Ah-Ng Kong

  2. Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA

    Yuqing Yang, Irene Yang, Mingnan Cao, Zheng-yuan Su, Renyi Wu, Yue Guo & Ah-Ng Kong

  3. State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, 100191, Beijing, People’s Republic of China

    Mingnan Cao

  4. Department of Bioscience Technology, Chung Yuan Christian University, 200 Chung Pei Road, Chung Li District, Taoyuan City, 32023, Taiwan, Republic of China

    Zheng-yuan Su

  5. Environmental and Occupational Health Sciences Institute, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, 08854, USA

    Mingzhu Fang

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  1. Yuqing Yang
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Yang, Y., Yang, I., Cao, M. et al. Fucoxanthin Elicits Epigenetic Modifications, Nrf2 Activation and Blocking Transformation in Mouse Skin JB6 P+ Cells. AAPS J 20, 32 (2018). https://doi.org/10.1208/s12248-018-0197-6

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  • DOI: https://doi.org/10.1208/s12248-018-0197-6

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