Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP Mice

Siwang Yu, Tin Oo Khor, Ka Lung Cheung, Wenge Li, Tien Yuan Wu, Ying Huang, Barbara A. Foster, Yuet Wai Kan, Ah Ng Kong

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a transcription factor which regulates the expression of many cytoprotective genes. In the present study, we found that the expression of Nrf2 was suppressed in prostate tumor of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice. Similarly, the expression of Nrf2 and the induction of NQO1 were also substantially suppressed in tumorigenic TRAMP C1 cells but not in non-tumorigenic TRAMP C3 cells. Examination of the promoter region of the mouse Nrf2 gene identified a CpG island, which was methylated at specific CpG sites in prostate TRAMP tumor and in TRAMP C1 cells but not in normal prostate or TRAMP C3 cells, as shown by bisulfite genomic sequencing. Reporter assays indicated that methylation of these CpG sites dramatically inhibited the transcriptional activity of the Nrf2 promoter. Chromatin immunopreceipitation (ChIP) assays revealed increased binding of the methyl-CpG-binding protein 2 (MBD2) and trimethyl-histone H3 (Lys9) proteins to these CpG sites in the TRAMP C1 cells as compared to TRAMP C3 cells. In contrast, the binding of RNA Pol II and acetylated histone H3 to the Nrf2 promoter was decreased. Furthermore, treatment of TRAMP C1 cells with DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine (5-aza) and histone deacetylase (HDAC) inhibitor trichostatin A (TSA) restored the expression of Nrf2 as well as the induction of NQO1 in TRAMP C1 cells. Taken together, these results indicate that the expression of Nrf2 is suppressed epigenetically by promoter methylation associated with MBD2 and histone modifications in the prostate tumor of TRAMP mice. Our present findings reveal a novel mechanism by which Nrf2 expression is suppressed in TRAMP prostate tumor, shed new light on the role of Nrf2 in carcinogenesis and provide potential new directions for the detection and prevention of prostate cancer.

Original languageEnglish (US)
Article numbere8579
JournalPLoS One
Volume5
Issue number1
DOIs
StatePublished - Jan 5 2010
Externally publishedYes

Fingerprint

prostatic neoplasms
adenocarcinoma
Epigenomics
epigenetics
Transgenic Mice
Tumors
Prostate
Prostatic Neoplasms
Adenocarcinoma
Methyl-CpG-Binding Protein 2
genetically modified organisms
Histones
Methylation
decitabine
mice
Assays
trichostatin A
Genes
CpG Islands
Histone Deacetylase Inhibitors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Yu, S., Khor, T. O., Cheung, K. L., Li, W., Wu, T. Y., Huang, Y., ... Kong, A. N. (2010). Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP Mice. PLoS One, 5(1), [e8579]. https://doi.org/10.1371/journal.pone.0008579

Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP Mice. / Yu, Siwang; Khor, Tin Oo; Cheung, Ka Lung; Li, Wenge; Wu, Tien Yuan; Huang, Ying; Foster, Barbara A.; Kan, Yuet Wai; Kong, Ah Ng.

In: PLoS One, Vol. 5, No. 1, e8579, 05.01.2010.

Research output: Contribution to journalArticle

Yu, S, Khor, TO, Cheung, KL, Li, W, Wu, TY, Huang, Y, Foster, BA, Kan, YW & Kong, AN 2010, 'Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP Mice', PLoS One, vol. 5, no. 1, e8579. https://doi.org/10.1371/journal.pone.0008579
Yu, Siwang ; Khor, Tin Oo ; Cheung, Ka Lung ; Li, Wenge ; Wu, Tien Yuan ; Huang, Ying ; Foster, Barbara A. ; Kan, Yuet Wai ; Kong, Ah Ng. / Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP Mice. In: PLoS One. 2010 ; Vol. 5, No. 1.
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