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

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 (?) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1? 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.

SUBMITTER: Amelio I 

PROVIDER: S-EPMC4291637 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature