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

Abstract

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)

DNA methylation of the CYP1A1 enhancer is associated with smoking‐induced genetic alterations in human lung

“…Based on previous studies, DNA methylation of these regions may regulate CYP1A1 mRNA levels. 19,21,22 A total of 120 adjacent histologically normal human lung tissue samples from early stage lung cancer patients were analyzed (Table 1). In all tissues, the region A of the enhancer was more methylated [33.14% 6 4.42 (mean 6 SEM)] than the region B (2.54% 6 0.57).…”

“…17,18 In vitro, methylation of cytosine-phosphate-guanosine (CpG) in the XRE inhibits binding of the AHR complex and DNA methylation may regulate CYP1A1 expression in different human tissues. [19][20][21][22][23] We hypothesized that DNA methylation could be involved in inter-individual differences in CYP1A1 gene expression in human lung and play a role in lung cancer development. We quantitatively assess the DNA methylation levels of the CYP1A1 enhancer in histologically normal and tumor lung tissues as well as in a panel of human lung cells.…”

Clinical, Cytogenetic and CYP1A1 exon-1 Gene Mutation Analysis of Beedi Workers in Vellore Region, Tamil Nadu

“…Moreover, induction of the enzymes in humans exhibits large variations (Ma and Lu 2003). Methylation of the CYP1A1 promoter is already associated with prostate and lung cancers (Okino et al, 2006;Tekpli et al, 2012) an association between CYP1A1 polymorphisms and expression may occur through either changes in metabolism of estrogen or through changes in the metabolism of the environmental toxin. With regards to estrogen metabolism, CYP1A1 has been predominantly identified as being involved in the formation of the 2-hydroxyestrogens, which exhibit lower estrogenic activity than the 4-hydroxyestrogens and 16-alpha-hydroxy estrogens, metabolites that are believed to increase cancer risk (Cribb, 2006).…”

Perinatal Exposure to Environmental Chemicals Induces Epigenomic Changes in Offspring

“…In our laboratory, we demonstrated that C57BL/6J mice administered TCDD during the fetal stage showed a higher incidence of forestomach cancer due to BaP injection and enhanced induction of Cyp1a1 mRNA by TCDD re-administration in adulthood. Methyl-CpGs level of the Cyp1a1 promoter region, which includes Ahr-binding xenobiotic response elements, is involved in TCDD induced transcription activity in LNCaP cells (48). The methylation frequency of the Cyp1a1 promoter region in the liver DNA of mice exposed to TCDD was signiˆcantly lower than that of the control mice.…”