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AAPS J. 2017 Mar;19(2):421-430. doi: 10.1208/s12248-016-0016-x. Epub 2016 Dec 2.

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

Yang Y1,2,3, Fuentes F1,2, Shu L1,2, Wang C1,2, Pung D1,2,3, Li W1,2, Zhang C1,2,3, Guo Y1,2,3, Kong AN4,5,6.

Author information

1
Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Piscataway, New Jersey, USA.
2
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Piscataway, New Jersey, USA.
3
Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, 08854, USA.
4
Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Piscataway, New Jersey, USA. kongt@pharmacy.rutgers.edu.
5
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Piscataway, New Jersey, USA. kongt@pharmacy.rutgers.edu.
6
Ernest Mario School of Pharmacy, Room 228, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA. kongt@pharmacy.rutgers.edu.

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.

KEYWORDS:

DNA methylation; GSTP1; astaxanthin; epigenetics; prostate cancer

PMID:
27913949
DOI:
10.1208/s12248-016-0016-x
[Indexed for MEDLINE]

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