Abstract
The functional significance of the overexpression of unmutated TAp73, a homologue of the tumour suppressor p53, in multiple human cancers is unclear, but raises the possibility of unidentified roles in promoting tumorigenesis. We show here that TAp73 is stabilized by hypoxia, a condition highly prevalent in tumours, through HIF-1α-mediated repression of the ubiquitin ligase Siah1, which targets TAp73 for degradation. Consequently, TAp73-deficient tumours are less vascular and reduced in size, and conversely, TAp73 overexpression leads to increased vasculature. Moreover, we show that TAp73 is a critical regulator of the angiogenic transcriptome and is sufficient to directly activate the expression of several angiogenic genes. Finally, expression of TAp73 positively correlates with these angiogenic genes in several human tumours, and the angiogenic gene signature is sufficient to segregate the TAp73(Hi)- from TAp73(Low)-expressing tumours. These data demonstrate a pro-angiogenic role for TAp73 in supporting tumorigenesis, providing a rationale for its overexpression in cancers.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Hypoxia
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Female
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Gene Expression Regulation, Neoplastic
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HCT116 Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, SCID
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Neoplasms / blood supply*
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Neovascularization, Pathologic / genetics*
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Protein Binding
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Tumor Protein p73
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin-Protein Ligases / antagonists & inhibitors*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitination
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Vascular Endothelial Growth Factor A / biosynthesis
Substances
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DNA-Binding Proteins
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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Trp73 protein, mouse
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Tumor Protein p73
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Tumor Suppressor Proteins
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Ubiquitin-Protein Ligases
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seven in absentia proteins
Associated data
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GEO/GSE11673
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GEO/GSE15460
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GEO/GSE62236