Translational Activation of HIF1α by YB-1 Promotes Sarcoma Metastasis

Cancer Cell. 2015 May 11;27(5):682-97. doi: 10.1016/j.ccell.2015.04.003.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Y-Box-Binding Protein 1
  • YBX1 protein, human
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human