Role of epigenetic deregulation in hematogenous dissemination of malignant uveal melanoma.

It has become increasingly clear that epigenetic deregulation plays a fundamental role in cancer. Although the understanding of molecular, genetic and transcriptional alterations involved in the initiation and progression of uveal melanoma (UM) has grown significantly in recent years, little attention has been paid to the role of epigenetic changes. In cancer, epithelial-to-mesenchymal transition (EMT) enables trans-differentiation of epithelial tumor cells, endowing them with migratory and invasive properties. EMT-inducing transcription factors have been shown to interact with multiple epigenetic modifiers, thus reflecting the reversible nature of EMT. Therefore, the epigenetic therapy targeting these interactions may provide a promising therapeutic option, especially since no improvement in survival of patients with metastatic UM has been achieved using traditional approaches. This review summarizes current knowledge of epigenetic regulation of EMT in UM and emphasizes the need for deeper understanding of these highly dynamic and reversible processes. The potential for targeting individual members of the epigenetic machinery is also addressed.

Global and gene specific DNA methylation in breast cancer cells was not affected during epithelial-to-mesenchymal transition in vitro.

Epithelial-to-mesenchymal transition (EMT) significantly affects the risk of metastasising in breast cancer. Plasticity and reversibility of EMT suggest that epigenetic mechanisms could be the key drivers of these processes, but little is known about the dynamics of EMT-related epigenetic alterations. We hypothesised that EMT, mediated by autocrine and paracrine signals, will be accompanied by changes in DNA methylation profiles. Therefore, conditioned medium from adipose tissue-derived mesenchymal stromal cells was used for induction of EMT in human breast cancer SK-BR-3 cell line. EMT-related morphological alterations and changes in gene expression of EMT-associated markers were assessed. To reverse EMT, 20 nm size gold nanoparticles (AuNPs) synthesized by the citrate reduction method were applied. Finally, DNA methylation of LINE-1 sequences and promoter methylation of TIMP3, ADAM23 and BRMS1 genes were quantitatively evaluated by pyrosequencing. Despite the presence of EMT-associated morphological and gene expression changes in tumour cells, EMT induced by adipose tissue-derived mesenchymal stromal cells had almost no effect on LINE-1 and gene-specific DNA methylation patterns of TIMP3, ADAM23 and BRMS1 genes. Although treatment for 24, 48 or 72 hours with 20 nm AuNPs at a concentration of 3 µg/ml slightly decreased gene expression of EMT-associated markers in SK-BR-3 cells, it did not alter global or gene-specific DNA methylation. Our results suggest that changes in DNA methylation are not detectable in vitro in early phases of EMT. Previously published positive findings could represent rather the sustained presence of potent EMT-inducing signals or the synergistic effect of various epigenetic mechanisms. Treatment with AuNPs slightly attenuated EMT, and their therapeutic potential needs to be further investigated.