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Translational Activation of HIF1α by YB-1 Promotes Sarcoma Metastasis

2015; Cell Press; Volume: 27; Issue: 5 Linguagem: Inglês

10.1016/j.ccell.2015.04.003

1878-3686

Amal M. El-Naggar, Chansey J. Veinotte, Hongwei Cheng, Thomas G. P. Grünewald, Gian Luca Negri, Syam Prakash Somasekharan, Dale Corkery, Franck Tirode, Joan Mathers, Debjit Khan, Alastair H. Kyle, Jennifer H.E. Baker, Nancy E. LePard, Steven McKinney, Shamil Hajee, Momir Bosiljcic, Gabriel Leprivier, Cristina E. Tognon, Andrew I. Minchinton, Kevin L. Bennewith, Olivier Delattre, Yuzhuo Wang, Graham Dellaire, Jason N. Berman, Poul H. Sorensen,

Cryospheric studies and observations

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.