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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-01, Vol.112 (1), p.226-231
• Main Authors: Amelio, Ivano, Inoue, Satoshi, K. Markert, Elke, Levine, Arnold J., Knight, Richard A., W. Mak, Tak, Melino, Gerry
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Animals; Biological Sciences; Cell Line, Tumor; Disease Progression; DNA-Binding Proteins - metabolism; 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
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1410609111

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. Significance Adaptation to hypoxia promotes cancer progression, resulting in enhanced patient mortality. Activation of hypoxia-inducible factor 1 (HIF-1) leads to a transcriptional switch, which, regulating angiogenesis, metabolism, and survival, results in hypoxia adaptation. In cancer, increased HIF-1 levels can be a result of either intratumoral hypoxia or the altered function of tumor suppressors. Our study demonstrates that the tumor suppressor TAp73, a member of the p53 family of genes, opposes HIF-1 activation in cancer cells, resulting in reduced angiogenesis and tumor progression. TAp73-depleted mice show increased tumorigenicity, associated with increased HIF-1 signaling and angiogenesis. Expression of TAp73 in human cancers predicts good survival outcome and retrocorrelates with HIF-1 expression and activation. The TAp73/HIF-1 axis plays a critical role in cancer pathogenesis.