Melanoma tumor cells shift between proliferative and invasive states based on their plasticity and microenvironmental conditions. Our team has shown that melanoma cells, grown as spheroids in a neural cell crest medium, polarize toward an invasive phenotype, characterized by a higher motility, a poor proliferation rate and a gain of pluripotency gene expression (Nanog and Oct4) when compared with cells grown in two dimensions in a serum-contaning medium. In agreement with the phenotypic switching hypothesis, most of these features are reversible. Microarray studies comparing two- vs. three-dimensional cultures revealed the downregulation of a polycomb-like protein, PHF19 (PHD finger protein 19), in the spheroids. As Polycomb proteins are involved in the epigenetic control of gene expression, we hypothesized that PHF19 might play a role in the switch between proliferative and invasive phenotypes. In this report, we show that PHF19 silencing reduces the cell proliferation rate and increases the transendothelial migration capacities of melanoma cell lines. However, PHF19 does not modulate the transcription level of Oct4 and Nanog. In the search of an upstream transcriptional regulator of the above genes, we identified the Akt signaling cascade as an inhibitor of Oct4 and Nanog expression and an activator for PHF19 expression. Through chromatin immunoprecipitation, we further provide evidence that phospho-Akt is part of the transcriptional complex associated to the promoters of all three genes. Our data therefore indicate the role of PHF19 and its upstream regulator, Akt, in the phenotype switch of melanoma cells from proliferative to invasive states.