Abstract
BackgroundEfficient treatments against metastatic melanoma dissemination are still lacking. Here, we report that low-cytotoxic concentrations of 5-aza-2′-deoxycytidine, a DNA demethylating agent, prevent in vitro 3D invasiveness of metastatic melanoma cells and reduce lung metastasis formation in vivo.ResultsWe unravelled that this beneficial effect is in part due to MIR-199A2 re-expression by promoter demethylation. Alone, this miR showed an anti-invasive and anti-metastatic effect. Throughout integration of micro-RNA target prediction databases with transcriptomic analysis after 5-aza-2′-deoxycytidine treatments, we found that miR-199a-3p downregulates set of genes significantly involved in invasion/migration processes. In addition, analysis of data from melanoma patients showed a stage- and tissue type-dependent modulation of MIR-199A2 expression by DNA methylation.ConclusionsThus, our data suggest that epigenetic- and/or miR-based therapeutic strategies can be relevant to limit metastatic dissemination of melanoma.
Highlights
Efficient treatments against metastatic melanoma dissemination are still lacking
We report that MIR-199A2 locus is under epigenetic regulation in a metastatic melanoma model and it is reactivated by promoter demethylation by 5azadC
In conclusion, we proved that slightly cytotoxic doses of 5azadC are translated into an anti-invasive effect in a BRAF-mutated metastatic melanoma model
Summary
Efficient treatments against metastatic melanoma dissemination are still lacking. Here, we report that low-cytotoxic concentrations of 5-aza-2′-deoxycytidine, a DNA demethylating agent, prevent in vitro 3D invasiveness of metastatic melanoma cells and reduce lung metastasis formation in vivo. Since 2011, new targeted therapies against mutated BRAF (vemurafenib) and immunotherapies such as anti-CTLA4 (ipilimumab) and anti-PD1/PD-L1 antibodies emerged, giving very promising long-term responses. In the past few years, various studies reported on epigenetic alterations in metastatic melanoma, DNA methylation, and associated them with disease progression [4,5,6,7,8,9]. Specific methylation signatures were found for melanoma tumours harbouring BRAF mutations [8, 14]. The use of an epigenetic strategy, combined with relevant CpG island methylator phenotype (CIMP) [15] as markers for the prediction of prognosis or therapeutic response, could be envisioned for metastatic melanoma treatment [10, 16, 17]
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