Breast cancer epigenetics: from DNA methylation to microRNAs

Abstract

Both appropriate DNA methylation and histone modifications play a crucial role in the maintenance of normal cell function and cellular identity. In cancerous cells these "epigenetic belts" become massively perturbed, leading to significant changes in expression profiles which confer advantage to the development of a malignant phenotype. DNA (cytosine-5)-methyltransferase 1 (Dnmt1), Dnmt3a and Dnmt3b are the enzymes responsible for setting up and maintaining DNA methylation patterns in eukaryotic cells. Intriguingly, DNMTs were found to be overexpressed in cancerous cells, which is believed to partly explain the hypermethylation phenomenon commonly observed in tumors. However, several lines of evidence indicate that further layers of gene regulation are critical coordinators of DNMT expression, catalytic activity and target specificity. Splice variants of DNMT transcripts have been detected which seem to modulate methyltransferase activity. Also, the DNMT mRNA 3'UTR as well as the coding sequence harbors multiple binding sites for trans-acting factors guiding post-transcriptional regulation and transcript stabilization. Moreover, microRNAs targeting DNMT transcripts have recently been discovered in normal cells, yet expression of these microRNAs was found to be diminished in breast cancer tissues. In this review we summarize the current knowledge on mechanisms which potentially lead to the establishment of a DNA hypermethylome in cancer cells.

Fig. 1

Schematic representation of factors that potentially influence abundance of the de novo methyltransferase Dnmt3b in tumorous cells. In normal cells (left), physiological DNMT3B transcript levels are maintained by inhibitory miR-29 (a–c), miR-148 and translational inhibitor AUF1, which co-resides with the stabilization factor HuR in the 3′UTR of the mRNA. In tumorous cells (right), miR-29 and miR-148 are frequently abolished. Elevated levels of HuR may occupy the 3′UTR, thus preventing the binding of translational inhibitors. In the nucleus, Dnmt3b activity is further stimulated by binding of the catalytically inactive Dnmt3L as well as products from DNMT3B splice variants and aberrantly truncated Dnmt3b proteins (asterisks). Green color indicates stimulation/activation; red color indicates inhibition. Open circles, unmethylated DNA; filled circles, methylated DNA. For references see text.