Here, by inactivation the genes encoding the β (ACTB) and γ (ACTG1) actins with the help of the RNA-guided D10A mutated Cas9 nuclease gene editing, CRISPR/Cas9(D10A), system in A375 cells, we report, for the first time, that the lack of γ actin had the most severe consequences on A375 cells and these non-muscle actins are unequal in their features, particularly their influence on the formation of focal adhesions (FAs) and protrusive structures and, thus, the motility of melanoma cells. This evidence concerns the gene ACTB and melanoma.