ABSTRACT
BACKGROUND: Aberrant global DNA methylation is shown to increase cancer risk. LINE-1 has been proven a measure of global DNA methylation. The objectives of this study were to assess the association between LINE-1 methylation level and bladder cancer risk and to evaluate effect modification by environmental and genetic factors. METHODS: Bisulphite-treated leukocyte DNA from 952 cases and 892 hospital controls was used to measure LINE-1 methylation level at four CpG sites by pyrosequencing. Logistic regression model was fitted to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Interactions between LINE-1 methylation levels and environmental and genetic factors were assessed. RESULTS: The risk of bladder cancer followed a nonlinear association with LINE-1 methylation. Compared with subjects in the middle tertile, the adjusted OR for subjects in the lower and the higher tertiles were 1.26 (95% CI 0.99-1.60, P=0.06) and 1.33 (95% CI 1.05-1.69, P=0.02), respectively. This association significantly increased among individuals homozygous for the major allele of five single-nucleotide polymorphisms located in the phosphatidylethanolamine N-methyltransferase gene (corrected P-interaction<0.05). CONCLUSIONS: The findings from this large-scale study suggest that both low and high levels of global DNA methylation are associated with the risk of bladder cancer.
Subject(s)
DNA Methylation/genetics , Long Interspersed Nucleotide Elements/genetics , Phosphatidylethanolamine N-Methyltransferase/genetics , Urinary Bladder Neoplasms/genetics , Aged , Aged, 80 and over , CpG Islands/genetics , Female , Genetic Association Studies , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Leukocytes/pathology , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , Urinary Bladder Neoplasms/pathologyABSTRACT
The bromodomain protein BRD4 is involved in cell proliferation and cell cycle progression, primarily through its role in acetylated chromatin-dependent regulation of transcription at targeted loci. Here, we show that BRD4 is frequently downregulated by aberrant promoter hypermethylation in human colon cancer cell lines and primary tumors. Ectopic re-expression of BRD4 in these colon cancer cell lines markedly reduced in vivo tumor growth, suggesting a role of BRD4 in human colon cancer.
