Epigenetic CpG Methylation of the Promoter and Reactivation of the Expression of GSTP1 by Astaxanthin in Human Prostate LNCaP Cells

Abstract

Astaxanthin (AST), a red dietary carotenoid, has synergistic antioxidant effects with polyunsaturated fatty acids at low concentrations via Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or Nrf2)/antioxidant response element (ARE) signaling. In addition, chromatin remodeling and DNA methylation-based gene silencing represent a common mechanism in prostate carcinogenesis and tumor progression from normal cells to pre-initiated cells and ultimately to invasive carcinoma. Therefore, the control of epigenetic modification and the transcriptional/translational control of the activation of Nrf2 and Nrf2-target genes, including glutathione S-transferases (GSTs), appear to be an important mechanism that protects cells against injuries from oxidative stress and cancer development. In this study, we aim to investigate the role of AST in reactivating the expression of Nrf2 and GSTP1 through epigenetic modification in human prostate LNCaP cells. Treatment with AST in human LNCaP cells reduced the methylation of 21 CpG sites of the GSTP1 CpG island but did not affect the three CpG sites of the Nrf2 promoter region. AST induced the mRNA expression and protein expression of both Nrf2 and GSTP1. It also increased the mRNA expression of NQO1 in sh-mock LNCaP cells but not in sh-SETD7 LNCaP cells. Furthermore, AST reduced the protein expression of DNMT3b and significantly inhibited DNMT and HDAC activities in vitro. Taken together, these results suggest that AST decreased the methylation status of the GSTP1, and these epigenetic modifying effects may originate from the decreasing activities of epigenetic modification enzymes, contributing to the overall beneficial health effects of AST.

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ACKNOWLEDGEMENTS

This study was supported in part by institutional funds and by R01-CA118947 and R01-CA152826 from the National Cancer Institute (NCI), ​R01 AT009152 from the National Center for Complementary and Integrative Health (NCCIH), and R01AT007065 from the National Center for Complementary and Alternative Medicines (NCCAM) and the Office of Dietary Supplements (ODS). We thank all the members in Dr. Ah-Ng Tony Kong’s lab for their helpful discussion in the preparation of this manuscript.

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Guest Editors: Ah-Ng Tony Kong and Chi Chen

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Yang, Y., Fuentes, F., Shu, L. et al. Epigenetic CpG Methylation of the Promoter and Reactivation of the Expression of GSTP1 by Astaxanthin in Human Prostate LNCaP Cells. AAPS J 19, 421–430 (2017). https://doi.org/10.1208/s12248-016-0016-x

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KEY WORDS

  • astaxanthin
  • DNA methylation
  • epigenetics
  • GSTP1
  • prostate cancer