Silencing of CYP1A1 Expression in Rabbits by DNA Methylation

Takahashi, Yoshiki; Suzuki, Chiharu; Kamataki, Tetsuya

doi:10.1006/bbrc.1998.8791

Cited by 46 publications

(22 citation statements)

References 16 publications

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“…Previous in vitro studies reveal that methylation of the internal CpG site within the DRE motif inhibits AhRC binding in an electrophoretic mobility shift assay and suppresses TCDD-inducible reporter gene activity (9,10). These findings show that DNA methylation directly inhibits DRE function.…”

Section: Discussionmentioning

confidence: 63%

“…AhRC interacts with DNAbinding sites, termed dioxin response elements (DRE), located on the CYP1A1 enhancer to mediate TCDD-inducible gene expression (7). All DRE sites contain a CpG dinucleotide (8), which, when methylated in vitro, inhibits AhRC binding in an electrophoretic mobility shift assay and suppresses TCDD-inducible reporter gene activity (9,10). These findings suggest that methylation of the CYP1A1 enhancer may suppress its TCDD responsiveness.…”

Section: Introductionmentioning

confidence: 99%

“…CYP1A1 methylation is also observed in human and rabbit cells grown in culture (10,12). Here, we study the influence of DNA methylation and chromatin structure on dioxin action and CYP1A1 expression in cancerous and noncancerous human prostate cell lines and tissue samples.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic Inactivation of the Dioxin-Responsive Cytochrome P4501A1 Gene in Human Prostate Cancer

Okino

Pookot

et al. 2006

Cancer Research

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2,3,7, dioxin) is a toxic environmental contaminant that works through dioxin response elements (DRE) to activate gene expression. We tested the hypothesis that cancer-related epigenetic changes suppress dioxin activation of the cytochrome P4501A1 (CYP1A1) gene. 5-Aza-2 ¶-deoxycytidine (5-aza-CdR), an inhibitor of DNA methylation, increases TCDD-inducible CYP1A1 mRNA expression in cancerous LNCaP cells but not in noncancerous PWR-1E and RWPE-1 cells (all human prostate cell lines). Bisulfite DNA sequencing shows that the TCDD-responsive CYP1A1 enhancer is highly methylated in LNCaP cells but not in RWPE-1 cells. In vivo footprinting experiments reveal that unmethylated DRE sites do not bind protein in response to TCDD in LNCaP cells, whereas inducible DRE occupancy occurs in RWPE-1 cells. Pretreatment of LNCaP cells with 5-aza-CdR partially restores TCDD-inducible DRE occupancy, showing that DNA methylation indirectly suppresses DRE occupancy. Chromatin immunoprecipitation experiments reveal that LNCaP cells lack trimethyl histone H3 lysine 4, a mark of active genes, on the CYP1A1 regulatory region, whereas this histone modification is prevalent in PWR-1E and RWPE-1 cells. We also analyzed CYP1A1 enhancer methylation in human prostate tissue DNA. We do not detect CYP1A1 enhancer methylation in 30 DNA samples isolated from noncancerous prostate tissue. In contrast, 11 of 30 prostate tumor DNA samples have detectable CYP1A1 enhancer methylation, indicating that it is hypermethylated in prostate tumors. This is the first report that shows that CYP1A1 is aberrantly hypermethylated in human prostate cancer and has an altered, inaccessible chromatin structure that suppresses its dioxin responsiveness. (Cancer Res 2006; 66(15): 7420-8)

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

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Epigenetic Inactivation of the Dioxin-Responsive Cytochrome P4501A1 Gene in Human Prostate Cancer

Okino

Pookot

et al. 2006

Cancer Research

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“…DNA methylation can directly interfere with the binding of specific transcription factors to their recognition sites in their respective promoters such as activator protein 2, c-Myc, and nuclear factor nB (17,32). In addition, Takahashi et al (33) have shown that the AhR/ARNT complex was not able to bind to methylated DREs. Our results show that several binding sites containing CpG dinucleotides are methylated in BPH samples.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 1B1 Is Overexpressed and Regulated by Hypomethylation in Prostate Cancer

Tokizane

Shiina

Igawa

et al. 2005

Clinical Cancer Research

173

101

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Purpose: Cytochrome P450 1B1 (CYP1B1), a dioxin inducible member of the CYP supergene family, is overexpressed in various human malignancies including prostate cancer. We hypothesized that promoter/enhancer CpG methylation contributes to the regulation of CYP1B1 expression in human prostate tissue. Experimental Design: Expression and induction of the CYP1B1 gene in clinical prostate tissues and prostate cancer cell lines were investigated. The methylation status of the CYP1B1 gene was analyzed in 175 prostate cancer and 96 benign prostatic hyperplasia samples using methylationspecific PCR (MSP) and bisulfite-modified DNA sequencing. MSP primers covered dioxin response elements (DRE) and Sp1sites that are important for the expression of CYP1B1. Results: Expressions of CYP1B1mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1. In prostate cancer cells, CYP1B1 mRNA was induced by 2,3,7,8-tetrachlorodigenzo-p-dioxin (TCDD) and/or demethylation agent (5-aza-2-deoxycytidine). There was no change in the expressions of AhR and ARNT. Methylation of promoter/enhancer regions was significantly higher in benign prostatic hyperplasia compared with prostate cancer. MSP-positive patients had significantly lower risk for prostate cancer as compared with MSP-negative patients. There was no correlation between CYP1B1 methylation status and clinicopathologic features. Conclusions: CYP1B1is overexpressed in prostate cancer and regulated by hypomethylation of its promoter/enhancer region. This is the first report about CYP1B1 regulation in human clinical prostate samples showing that hypomethylation of the CYP1B1 gene may play an important role in prostate cancer.

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“…This type of DNA methylation has been reported to be involved in the silencing of CYP1A1 gene expression in rabbit kidney cells. 36) We cannot rule out another possibility that AR in LNCaP may play some role in transcriptional activation mediated through AhR because a previous study has reported that LNCaP cells contain an AR with a point mutation in the steroid-binding domain (codon 868, Thr to Ala), which leads to a change in specificity of the AR. 37) Other studies of cell cycle checkpoints have suggested that AhR plays an important role in the regulation of cell growth and differentiation.…”

Section: Effect Of Hormone Receptor Status On Tcddinduced Xre Transacmentioning

confidence: 96%

Interaction between Dioxin Signaling and Sex Steroid Hormones

Sone

Yonemoto

2002

JOURNAL OF HEALTH SCIENCE

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Dioxin,2,3,7,, is an environmental contaminant that produces potent toxic effects in humans and animals. TCDD is carcinogenic at multiorgan sites and induces disorders of reproduction, development, and immunity. It has been considered that the effects of TCDD partly involve disruption of the endocrine system, since TCDD causes progressive endometriosis in the rhesus monkey, suppresses development of the male reproductive system and sexual dimorphism of the brain, and damages the ovaries. These effects suggest alteration of sex steroidogenesis in the target organs. To clarify the endocrine disruptive action of TCDD, many studies of its effects on estrogen-responsive cell lines have been conducted. This mini-review describes recent experiments conducted in the authors' laboratory and discusses our understanding of the molecular mechanisms of interaction between dioxin signaling and sex-steroid hormones, focusing on three issues: 1) influence of estrogen on TCDD-induced cytochrome P4501A1 (CYP1A1) protein in vivo; 2) influence of estrogen on TCDD-induced xenobiotic response element (XRE) transactivation in cultured cell systems; and 3) effect of hormone-receptor status on TCDD-induced XRE transactivation and its relation to the cell cycle.

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Silencing of CYP1A1 Expression in Rabbits by DNA Methylation

Cited by 46 publications

References 16 publications

Epigenetic Inactivation of the Dioxin-Responsive Cytochrome P4501A1 Gene in Human Prostate Cancer

Epigenetic Inactivation of the Dioxin-Responsive Cytochrome P4501A1 Gene in Human Prostate Cancer

Cytochrome P450 1B1 Is Overexpressed and Regulated by Hypomethylation in Prostate Cancer

Interaction between Dioxin Signaling and Sex Steroid Hormones

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