Y-box binding protein 1 (YB-1) is an oncogenic transcription and translation factor and is overexpressed in several types of
cancer. Our previous data showed that YB-1 is upregulated and translocated to the nucleus during
melanoma progression and that YB-1 is an important
transcription factor regulating proliferation, survival, migration, invasion and chemosensitivity of
melanoma cells. It has been suggested that YB-1 is activated and translocated to the nucleus after S102-phosphorylation in the
DNA binding domain. In this study, we show that activation of YB-1 by S102-phosphorylation and nuclear translocation is increased during
melanoma progression using a human tissue microarray with 100 melanocytic lesions. Furthermore, we analysed the mechanisms governing the expression and activity of YB-1 in
melanoma cells. We show that the PI3K/AKT and p53 signalling,
growth factors and chemotherapeutic agents increase YB-1 promoter activity. This, however, resulted in no or only modest increase in YB-1
protein expression. We show that the MAPK and PI3K/AKT signalling pathways, both activated in
melanoma cells, as well as p53 overexpression increase YB-1 S102-phosphorylation, whereas NFκB signalling inhibits phosphorylation. Overexpression of YB-1 in
melanoma cells inhibits translation efficiency and by this proliferation and survival of
melanoma cells indicating that there is an autoregulatory loop restricting YB-1
protein expression. These data suggest that there is a tightly regulated feedback mechanism regulating YB-1 expression and activation, necessary for proper cell cycle progression of
melanoma cells.