TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):226-31. doi: 10.1073/pnas.1410609111. Epub 2014 Dec 22.

Abstract

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer.

Keywords: VEGF; p53 family; p73; tumor progression; tumor vascularization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Animals
  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism*
  • Disease Progression
  • Gene Deletion
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • In Vitro Techniques
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice, Inbred C57BL
  • Neoplasms / blood supply*
  • Neoplasms / metabolism*
  • Neovascularization, Pathologic
  • Nuclear Proteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Proteolysis*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Signal Transduction
  • Survival Analysis
  • Tumor Protein p73
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitination
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • DNA-Binding Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • TP73 protein, human
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Proteins
  • Ubiquitin
  • Vascular Endothelial Growth Factor A
  • Proto-Oncogene Proteins c-mdm2
  • Proteasome Endopeptidase Complex