Translational Activation of HIF1α by YB-1 Promotes Sarcoma Metastasis

• DOI: 10.1016/j.ccell.2015.04.003
• Publication Date: 2015-05-11T15:45:16Z
• Authors: Amal M. El-Naggar; Chansey J. Veinotte; Hongwei Cheng; Thomas G.P. Grune...; Gian Luca Negri; Syam Prakash Soma...; Dale P. Corkery; Franck Tirode; Joan Mathers; Debjit Khan; Alastair H. Kyle; Jennifer H. 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
• Keywords: 0301 basic medicine; Cancer Research; Sarcoma; Cell Biology; Hypoxia-Inducible Factor 1, alpha Subunit; 3. Good health; 03 medical and health sciences; Oncology; Von Hippel-Lindau Tumor Suppressor Protein; Protein Biosynthesis; Humans; Neoplasm Invasiveness; Y-Box-Binding Protein 1; Neoplasm Metastasis

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.