YB-1 Expression and Phosphorylation Regulate Tumorigenicity and Invasiveness in Melanoma by Influencing EMT

• Published in: Molecular cancer research 2018-07, Vol.16 (7), p.1149-1160
• Main Authors: Kosnopfel, Corinna, Sinnberg, Tobias, Sauer, Birgit, Busch, Christian, Niessner, Heike, Schmitt, Anja, Forchhammer, Stephan, Grimmel, Cornelia, Mertens, Peter R, Hailfinger, Stephan, Dunn, Sandra E, Garbe, Claus, Schittek, Birgit
• Format: Article
• Language: English
• Subjects: Animals; Breast carcinoma; Cancer; Carcinogenesis - genetics; Cell culture; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; Chick Embryo; Epithelial-Mesenchymal Transition - genetics; Gene Expression Regulation, Neoplastic; Humans; Invasiveness; Localization; Melanoma; Melanoma - genetics; Melanoma - pathology; Melanoma, Cutaneous Malignant; Mesenchyme; Metastases; Metastasis; Mice; Neoplasm Invasiveness - genetics; Neural crest; Nuclear factor I; Phenotypes; Phosphorylation; Proteins; Serine; Skin cancer; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Tumorigenicity; Xenograft Model Antitumor Assays; Y-Box-Binding Protein 1 - genetics
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-17-0528

Cutaneous melanoma represents one of the most aggressive human tumor entities possessing a high tendency to metastasize. Cancer cells frequently exploit a highly conserved developmental program, the epithelial-to-mesenchymal transition (EMT), to gain migratory and invasive properties promoting their metastatic spread. Cytoplasmic localization of the oncogenic transcription and translation factor Y-box binding protein 1 (YB-1) is a powerful inducer of EMT in breast carcinoma cells. Interestingly, EMT-like processes have also been observed in cutaneous melanoma despite its neural crest origin. Here, increased expression of YB-1 negatively affects patient survival in malignant melanoma and promotes melanoma cell tumorigenicity both and Intriguingly, this effect seems to be mainly mediated by cytoplasmic YB-1 that does not exhibit phosphorylation at serine-102 (S102). Moreover, S102 unphosphorylated YB-1 enhances the migratory and invasive potential of human melanoma cells in two-dimensional (2D) and three-dimensional (3D) culture systems and facilitates acquisition of a mesenchymal-like invasive phenotype in the chick embryo model. Collectively, these data demonstrate that the cytoplasmic activity of YB-1 stimulates tumorigenicity and metastatic potential of melanoma cells by promoting EMT-like properties. This study reveals for the first time that YB-1 efficiently drives tumorigenicity and invasiveness of melanoma cells in its S102 unphosphorylated cytoplasmic state and that YB-1 expression represents a negative prognostic factor in primary melanoma patients. .