Translational Activation of HIF1α by YB-1 Promotes Sarcoma Metastasis

• Published in: Cancer cell 2015-05, Vol.27 (5), p.682-697
• Main Authors: El-Naggar, Amal M., Veinotte, Chansey J., Cheng, Hongwei, Grunewald, Thomas G.P., Negri, Gian Luca, Somasekharan, Syam Prakash, Corkery, Dale P., Tirode, Franck, Mathers, Joan, Khan, Debjit, Kyle, Alastair H., Baker, Jennifer H., LePard, Nancy E., McKinney, Steven, Hajee, Shamil, Bosiljcic, Momir, Leprivier, Gabriel, Tognon, Cristina E., Minchinton, Andrew I., Bennewith, Kevin L., Delattre, Olivier, Wang, Yuzhuo, Dellaire, Graham, Berman, Jason N., Sorensen, Poul H.
• Format: Article
• Language: English
• Subjects: Humans; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Neoplasm Invasiveness; Neoplasm Metastasis; Protein Biosynthesis; Sarcoma - genetics; Sarcoma - pathology; Von Hippel-Lindau Tumor Suppressor Protein - physiology; Y-Box-Binding Protein 1 - physiology
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2015.04.003

Metastatic 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. [Display omitted] •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 YB-1 binds DNA and RNA and has been shown to promote epithelial-to-mesenchymal transition and metastasis of carcinomas. El-Naggar et al. show that YB-1 also contributes to metastasis of high-risk sarcomas by binding to HIF1A mRNA and enhancing its translation.