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.
Highlights
Prostate cancer, as well as many other age-related cancers, is characterized by increased intracellular oxidative stress [1,2]
We found that certain CpG sites in the distal region of the CpG island were hypermethylated in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) tumor tissues as well as in tumorigenic TRAMP-C1 and -C2 cells, but not in normal prostatic tissue and non-tumorigenic TRAMPC3 cells
Bisulfiteconverted genomic DNA derived from 12 palpable prostate tumors of 24 weeks old TRAMP mice and 10 apparently normal prostate tissues of C57BL/6J mice was used as templates
Summary
As well as many other age-related cancers, is characterized by increased intracellular oxidative stress [1,2]. The impaired antioxidant defense system in carcinogenesis of prostate cancer has been gaining increased attentions. Down-regulation of GST by DNA methylation appears to be quite common in human prostate cancer that it has been developed as a diagnostic marker [5]. Recent studies from our laboratory and others have found that the expression levels of SOD, UGT1A1, NQO1 and several GST family genes were significantly suppressed in prostate tumors in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice [9,10,11]. The down-regulation of GST enzymes in human prostate cancer have been linked to the promoter hypermethylation of GST genes [5,12]; promoter DNA hypermethylation does not appear to cause GST gene repression in TRAMP tumors [9]. Down-regulation of nuclear factor-erythroid 2p45 (NF-E2)related factor 2 (Nrf2), a key regulator of cellular antioxidant enzymes, may be responsible for the transcriptional suppression of GSTs and other phase II detoxifying enzyme genes [11]
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