Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP mice. 2006 4

Cancer development has been linked to epigenetic modifications of cancer oncogenes and tumor suppressor genes; in advanced metastatic cancers, severe epigenetic modifications are present. We previously demonstrated that the progression of prostate tumors in TRAMP mice is associated with methylation silencing of the Nrf2 promoter and a reduced level of transcription of Nrf2 and Nrf2 target genes. Radix Angelicae Sinensis (RAS; Danggui) is a medicinal herb and health food supplement that has been widely used in Asia for centuries. Z-Ligustilide (Lig) is one of the bioactive components of RAS. We investigated the potential of Lig and RAS to restore Nrf2 gene expression through epigenetic modification in TRAMP C1 cells. Lig and RAS induced the mRNA and protein expression of endogenous Nrf2 and Nrf2 downstream target genes, such as HO-1, NQO1, and UGT1A1. Bisulfite genomic sequencing revealed that Lig and RAS treatment decreased the level of methylation of the first five CpGs of the Nrf2 promoter. A methylation DNA immunoprecipitation assay demonstrated that Lig and RAS significantly decreased the relative amount of methylated DNA in the Nrf2 gene promoter region. Lig and RAS also inhibited DNA methyltransferase activity in vitro. Collectively, these results suggest that Lig and RAS are able to demethylate the Nrf2 promoter CpGs, resulting in the re-expression of Nrf2 and Nrf2 target genes. Epigenetic modifications of genes, including Nrf2, may therefore contribute to the overall health benefits of RAS, including the anticancer effect of RAS and its bioactive component, Lig.
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PMID:Epigenetic reactivation of Nrf2 in murine prostate cancer TRAMP C1 cells by natural phytochemicals Z-ligustilide and Radix angelica sinensis via promoter CpG demethylation. 2344 43

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a phase II enzyme that participates in the detoxification of dopamine-derived quinone molecules and reactive oxygen species. Our prior work using a proteomic approach found that NQO1 protein levels were significantly decreased in stable hepatitis B virus (HBV)-producing hepatoma cells relative to the empty-vector-transfected controls. However, the mechanism and biological significance of the NQO1 suppression remain elusive. In this study we demonstrate that HBV X protein (HBx) induces epigenetic silencing of NQO1 in hepatoma cells through promoter hypermethylation via recruitment of DNA methyltransferase DNMT3A to the promoter region of the NQO1 gene. In HBV-related hepatocellular carcinoma (HCC) specimens, HBx expression was correlated negatively to NQO1 transcripts but positively to NQO1 promoter hypermethylation. Downregulation of NQO1 by HBx reduced intracellular glutathione levels, impaired mitochondrial function, and increased susceptibility of hepatoma cells to oxidative stress-induced cell injury. These results suggest a novel mechanism for HBV-mediated pathogenesis of chronic liver diseases, including HCC.
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PMID:Epigenetic silencing of NAD(P)H:quinone oxidoreductase 1 by hepatitis B virus X protein increases mitochondrial injury and cellular susceptibility to oxidative stress in hepatoma cells. 2392 Mar 13

Nrf2 is a crucial transcription factor that controls a critical anti-oxidative stress defense system and is implicated in skin homeostasis. Apigenin (API), a potent cancer chemopreventive agent, protects against skin carcinogenesis and elicits multiple molecular signaling pathways. However, the potential epigenetic effect of API in skin cancer chemoprotection is not known. In this study, bisulfite genomic DNA sequencing and methylated DNA immunoprecipitation were utilized to investigate the demethylation effect of API at 15 CpG sites in the Nrf2 promoter in mouse skin epidermal JB6 P + cells. In addition, qPCR and Western blot analyses were performed to evaluate the mRNA and protein expression of Nrf2 and the Nrf2 ARE downstream gene, NQO1. Finally, the protein expression levels of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) were evaluated using API and the DNMT/HDAC inhibitor 5-aza/ trichostatin A. Our results showed that API effectively reversed the hypermethylated status of the 15 CpG sites in the Nrf2 promoter in a dose-dependent manner. API enhanced the nuclear translocation of Nrf2 and increased the mRNA and protein expression of Nrf2 and the Nrf2 downstream target gene, NQO1. Furthermore, API reduced the expression of the DNMT1, DNMT3a, and DNMT3b epigenetic proteins as well as the expression of some HDACs (1-8). Taken together, our results showed that API can restore the silenced status of Nrf2 in skin epidermal JB6 P + cells by CpG demethylation coupled with attenuated DNMT and HDAC activity. These results may provide new therapeutic insights into the prevention of skin cancer by dietary phytochemicals.
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PMID:Apigenin reactivates Nrf2 anti-oxidative stress signaling in mouse skin epidermal JB6 P + cells through epigenetics modifications. 2483 Sep 44

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a vital transcription factor that regulates the anti-oxidative defense system. Previous reports suggested that the expression of the Nrf2 gene can be regulated by epigenetic modifications. The potential epigenetic effect of taxifolin (TAX), a potent cancer chemopreventive agent, in skin cancer chemoprotection is unknown. In this study, we investigated how Nrf2 is epigenetically regulated by TAX in JB6 P+ cells. TAX was found to inhibit the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced colony formation of JB6 P+ cells. TAX induced antioxidant response element (ARE)-luciferase activity in HepG2-C8 cells and up-regulated mRNA and protein levels of Nrf2 and its downstream genes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1), in JB6 P+ cells. Furthermore, bisulfite genomic sequencing revealed that TAX treatment reduces the methylation level of the first 15 CpGs sites in the Nrf2 promoter. Western blotting showed that TAX inhibits the expression levels of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) proteins. In summary, our results revealed that TAX can induce expression of Nrf2 and its downstream target genes in JB6 P+ cells by CpG demethylation. These finding suggest that TAX may exhibit a skin cancer preventive effect by activating Nrf2 via an epigenetic pathway.
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PMID:Taxifolin Activates the Nrf2 Anti-Oxidative Stress Pathway in Mouse Skin Epidermal JB6 P+ Cells through Epigenetic Modifications. 2871 38

Excessive consumption of analgesic drug acetaminophen (APAP) can cause severe oxidative stress-mediated liver injury. Here, we investigated the protective effect and mechanism of aged citrus peel (Chenpi, CP), a Chinese herb usually used in foods in Asia, against APAP-induced hepatotoxicity. CP water (CP-WE), ethanolic (CP-EE), and water extraction residue ethanolic (CP-WREE) extracts were prepared. We found that CP-WREE contained higher content of bioactive flavonoids, including narirutin, nobiletin, and tangeretin, and more effectively enhanced the Nrf2 pathway in ARE-luciferase reporter gene transfected human HepG2-C8 cells. In mouse AML-12 hepatocytes, CP-WREE minimized APAP-induced damage and lipid peroxidation and increased mRNA and protein expressions of Nrf2 and its downstream defense enzymes (HO-1, NQO1, and UGT1A). CP-WREE also downregulated HDACs and DNMTs, upregulated KDMs, and increased the unmethylated Nrf2 promoter level. Additionally, CP-WREE blocked in vitro DNA methyltransferase activity. Taken together, CP-WREE might attenuate oxidative stress-induced hepatotoxicity through epigenetically regulating Nrf2-mediated cellular defense system.
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PMID:Aged Citrus Peel (Chenpi) Prevents Acetaminophen-Induced Hepatotoxicity by Epigenetically Regulating Nrf2 Pathway. 3179 43