期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：226-231
DOI：10.1073/pnas.1410609111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAdaptation 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. 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.
