Translational Activation of HIF1α by YB-1 Promotes Sarcoma Metastasis

• YB-1 expression is elevated in high-risk human sarcomas
• YB-1 promotes sarcoma invasion and metastasis
• YB-1 regulates HIF1α expression by directly promoting its mRNA translation
• YB-1 effects on sarcoma invasion and metastasis are mediated by HIF1α

SummaryMetastatic dissemination is the leading cause of death in cancer patients, which is particularly evident for high-risk sarcomas such as Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. Previous research identified a crucial role for YB-1 in the epithelial-to-mesenchymal transition (EMT) and metastasis of epithelial malignancies. Based on clinical data and two distinct animal models, we now report that YB-1 is also a major metastatic driver in high-risk sarcomas. Our data establish YB-1 as a critical regulator of hypoxia-inducible factor 1α (HIF1α) expression in sarcoma cells. YB-1 enhances HIF1α protein expression by directly binding to and activating translation of HIF1A messages. This leads to HIF1α-mediated sarcoma cell invasion and enhanced metastatic capacity in vivo, highlighting a translationally regulated YB-1-HIF1α axis in sarcoma metastasis.

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