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The AAPS Journal

, 20:32 | Cite as

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

  • Yuqing Yang
  • Irene Yang
  • Mingnan Cao
  • Zheng-yuan Su
  • Renyi Wu
  • Yue Guo
  • Mingzhu Fang
  • Ah-Ng Kong
Research Article Theme: Natural Products Drug Discovery in Cancer Prevention
Part of the following topical collections:
  1. Theme: Natural Products Drug Discovery in Cancer Prevention

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.

KEY WORDS

Nrf2 epigenetics astaxanthin fucoxanthin skin cancer prevention 

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

Notes

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.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there are no conflicts of interest.

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Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Yuqing Yang
    • 1
    • 2
  • Irene Yang
    • 1
    • 2
  • Mingnan Cao
    • 1
    • 2
    • 3
  • Zheng-yuan Su
    • 1
    • 2
    • 4
  • Renyi Wu
    • 1
    • 2
  • Yue Guo
    • 1
    • 2
  • Mingzhu Fang
    • 5
  • Ah-Ng Kong
    • 1
    • 2
  1. 1.Center for Phytochemical Epigenome Studies, Ernest Mario School of PharmacyRutgers UniversityPiscatawayUSA
  2. 2.Department of Pharmaceutics, Ernest Mario School of PharmacyRutgers UniversityPiscatawayUSA
  3. 3.State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical SciencesPeking UniversityBeijingPeople’s Republic of China
  4. 4.Department of Bioscience TechnologyChung Yuan Christian UniversityTaoyuan CityRepublic of China
  5. 5.Environmental and Occupational Health Sciences Institute, Ernest Mario School of PharmacyRutgers UniversityPiscatawayUSA

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