Abstract
miRNAs are important regulators of gene expression that are frequently deregulated in cancer, with aberrant DNA methylation being an epigenetic mechanism involved in this process. We previously identified miRNA promoter regions active in normal mammary cell types and here we analyzed which of these promoters are targets of aberrant DNA methylation in human breast cancer cell lines and breast tumor specimens. Using 5-methylcytosine immunoprecipitation coupled to miRNA tiling microarray hybridization, we performed comprehensive evaluation of DNA methylation of miRNA gene promoters in breast cancer. We found almost one third (55/167) of miRNA promoters were targets for aberrant methylation in breast cancer cell lines. Breast tumor specimens displayed DNA methylation of majority of these miRNA promoters, indicating that these changes in DNA methylation might be clinically relevant. Aberrantly methylated miRNA promoters were, similar to protein coding genes, enriched for promoters targeted by polycomb in normal cells. Detailed analysis of selected miRNA promoters revealed decreased expression of miRNA linked to increased promoter methylation for mir-31, mir-130a, let-7a-3/let-7b, mir-155, mir-137 and mir-34b/mir-34c genes. The proportion of miRNA promoters we found aberrantly methylated in breast cancer is several fold larger than that observed for protein coding genes, indicating an important role of DNA methylation in miRNA deregulation in cancer.
Highlights
MicroRNAs are short single-stranded RNA molecules that regulate gene expression at the posttranscriptional level by stimulating the degradation or inhibiting translation of target mRNAs [1]
Our results show that miRNA genes are frequent targets of aberrant DNA methylation in cancer; the resulting deregulation of miRNA levels likely contributes to human breast carcinogenesis
DNA methylation of miRNA promoters was analyzed in seven breast cancer cell lines and twelve breast tumor tissue specimens as well as in three cultured normal finite lifespan human mammary epithelial cells (HMEC) strains and five breast non-tumor tissue specimens, using 5-methylcytosine immunoprecipitation coupled to custom tiling microarray covering miRNA gene regions
Summary
MicroRNAs (miRNA) are short single-stranded RNA molecules that regulate gene expression at the posttranscriptional level by stimulating the degradation or inhibiting translation of target mRNAs [1]. Aberrant DNA methylation linked to silencing of individual miRNA genes has been found in many cancer types including breast cancer [4,9,10,11,12,13,14,15,16,17] Some of these miRNAs function as tumor suppressors [16,17] and their down regulation due to aberrant DNA methylation is associated with increased malignancy or metastatic potential in breast cancer [4,14,16,17]. These reports illustrate the importance of epigenetic deregulation of miRNA expression in carcinogenesis; to our knowledge, a comprehensive analysis of DNA methylation of miRNA genes in breast cancer has not been reported
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