Melanoma cells develop adaptive responses in order to cope with particular conditions of tumor microenvironment, characterized by stress conditions and deregulated proliferation.,Recently, the interplay between the stress response and the gene expression programs leading to metastatic spread has been reported.,We evaluated levels and localization of eIF2α/peIF2α in V600BRAF and wtBRAF metastatic melanoma cell lines by means of western blot and confocal microscopy analyses.,Furthermore, we performed a sequence analyses and structure and dynamics studies of eIF2α protein to reveal the role of eIF2α and its correlations in different pathways involved in the invasive phase of melanoma.,We found peIF2α both in cytoplasm and nucleus.,Nuclear localization was more represented in V600BRAF melanoma cell lines.,Our studies on eIF2α protein sequence indicated the presence of a predicted bipartite NLS as well as a nuclear export signal NES and an S1 domain, typical of RNA interacting proteins.,Furthermore, we found high levels of transcription factor EB (TFEB), a component of the MiT/TFE family, and low β-catenin levels in V600BRAF cells.,Based on our results, we suggest that peIF2α nuclear localization can be crucial in ER stress response and in driving the metastatic spread of melanoma, through lysosomal signaling and Wnt/β-catenin pathway.,In conclusion, this is the first evidence of nuclear localization of peIF2α, representing a possible target for future therapeutic approaches for metastatic melanoma.,The online version of this article (10.1186/s12967-019-1772-z) contains supplementary material, which is available to authorized users.
Transcriptional reprogramming of proliferative melanoma cells into a phenotypically distinct invasive cell subpopulation is a critical event at the origin of metastatic spreading.,Here we generate transcriptome, open chromatin and histone modification maps of melanoma cultures; and integrate this data with existing transcriptome and DNA methylation profiles from tumour biopsies to gain insight into the mechanisms underlying this key reprogramming event.,This shows thousands of genomic regulatory regions underlying the proliferative and invasive states, identifying SOX10/MITF and AP-1/TEAD as regulators, respectively.,Knockdown of TEADs shows a previously unrecognized role in the invasive gene network and establishes a causative link between these transcription factors, cell invasion and sensitivity to MAPK inhibitors.,Using regulatory landscapes and in silico analysis, we show that transcriptional reprogramming underlies the distinct cellular states present in melanoma.,Furthermore, it reveals an essential role for the TEADs, linking it to clinically relevant mechanisms such as invasion and resistance.,The key regulators that allow transition from proliferative to invasive phenotype in melanoma cells have not been identified yet.,The authors perform chromatin and transcriptome profiling followed by comprehensive bioinformatics analysis identifying new candidate regulators for two distinct cell states of melanoma.