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

Siwang Yu1, Tin Oo Khor, Ka-Lung Cheung

  • 1Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.

Plos One
|January 12, 2010
PubMed

Insights

Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) expression is epigenetically suppressed in prostate tumors. Promoter methylation and histone changes inhibit Nrf2, but DNMT and HDAC inhibitors restore its expression, offering new avenues for prostate cancer detection and prevention.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a key transcription factor regulating cytoprotective genes.
  • Nrf2 plays a crucial role in cellular defense mechanisms against oxidative stress and carcinogens.
  • Dysregulation of Nrf2 has been implicated in various cancers, including prostate cancer.

Purpose of the Study:

  • To investigate the mechanism of Nrf2 suppression in prostate tumors using the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model.
  • To elucidate the role of epigenetic modifications, specifically DNA methylation and histone alterations, in regulating Nrf2 expression in prostate cancer.
  • To explore the potential of epigenetic drugs in restoring Nrf2 function in prostate tumor cells.

Main Methods:

  • Analysis of Nrf2 and NQO1 expression in normal prostate and TRAMP mouse prostate tumors and cell lines (TRAMP C1 and TRAMP C3).
  • Bisulfite genomic sequencing to assess CpG island methylation in the Nrf2 promoter region.
  • Reporter assays to evaluate the impact of methylation on Nrf2 promoter activity.
  • Chromatin immunoprecipitation (ChIP) assays to detect binding of methyl-CpG-binding protein 2 (MBD2) and histone modifications.
  • Treatment of TRAMP C1 cells with DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (5-aza) and histone deacetylase (HDAC) inhibitor trichostatin A (TSA).

Main Results:

  • Nrf2 expression was significantly suppressed in TRAMP mouse prostate tumors and tumorigenic TRAMP C1 cells compared to normal prostate and non-tumorigenic TRAMP C3 cells.
  • CpG island methylation in the Nrf2 promoter was observed in TRAMP tumors and TRAMP C1 cells, correlating with reduced Nrf2 transcriptional activity.
  • Increased binding of MBD2 and trimethyl-histone H3 (Lys9) and decreased binding of RNA Pol II and acetylated histone H3 were found at the Nrf2 promoter in TRAMP C1 cells.
  • Treatment with 5-aza and TSA restored Nrf2 expression and NQO1 induction in TRAMP C1 cells.

Conclusions:

  • Epigenetic silencing, specifically promoter methylation associated with MBD2 and repressive histone modifications, underlies Nrf2 suppression in TRAMP mouse prostate tumors.
  • These findings reveal a novel epigenetic mechanism contributing to Nrf2 downregulation in prostate carcinogenesis.
  • The study suggests that targeting epigenetic pathways may offer a promising strategy for prostate cancer prevention and treatment by restoring Nrf2 function.

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