Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis


  • N. Rohwer
  • S. Jumpertz
  • M. Erdem
  • A. Egners
  • K.T. Warzecha
  • At. Fragoulis
  • A.A. Kühl
  • R. Kramann
  • S. Neuss
  • I. Rudolph
  • T. Endermann
  • C. Zasada
  • I. Apostolova
  • M. Gerling
  • S. Kempa
  • R. Hughes
  • C.E. Lewis
  • W. Brenner
  • M.B. Malinowski
  • M. Stockmann
  • L. Schomburg
  • W. Faller
  • O.J. Sansom
  • F. Tacke
  • M. Morkel
  • T. Cramer


  • Oncogene


  • Oncogene 38 (28): 5670-5685


  • The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1’s role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of Wnt/β-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts (TAF) and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with HIF-1α, arguing for an importance of hypoxia-independent, i.e., non-canonical, HIF-1 stabilization for intestinal tumorigenesis that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1α stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.