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

Abstract

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. .

Y-Box Binding Proteins in mRNP Assembly, Translation, and Stability Control

“…YB-1 activity in translation and stability can be modulated by YB-1 modification (Table 1), non-coding RNAs (Table 2), or subcellular localization. For example, YB-1 phosphorylation at Ser102 promotes the translation of growth-related mRNAs [75,107], while the overexpression of YB-1 is unable to be phosphorylated at Ser102 and promotes the translation of EMT-related genes [144]. YB-1 acetylation at Lys81 prevents HIF-1α and G3BP1 translation activation [125].…”

Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers

“…YB-1 is one of the rare proteins that regulates the cellular signaling pathways underlying nearly every cancer hallmark [ 2 , 3 ]. As both a cytoplasmic and nuclear protein, YB-1 is highly expressed in different cancer types, such as breast, lung, colorectal, melanocytic, prostate, ovary, and bone cancer [ 2 , 4 , 5 , 6 , 7 ]. In breast carcinomas, expression of cytoplasmic YB-1 has been shown to be associated with tumor aggressiveness, and nuclear localization was shown to be a predictive marker of recurrence after chemo- and radiotherapy [ 8 ].…”

YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling

“…YB-1 performs a wide variety of cellular functions and is involved in diverse biological processes, such as the regulation of transcription/translation, modification of chromatin, DNA repair, RNA packaging, and modulating cellular stress responses [ 2 ]. YB-1 controls cell cycle-dependent genes, and increased nuclear expression has been found in tumors [ 3 , 4 , 5 ]. In addition to its intracellular functions, YB-1 is secreted via a non-classical pathway following cytokine stimulation with either transforming growth factor β (TGF-β) or platelet-derived growth factor (PDGF) [ 6 , 7 ].…”