Hypoxia-inducible TAp73 supports tumorigenesis by regulating the angiogenic transcriptome

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.

The p53 family and the hypoxia-inducible factors (HIFs): determinants of cancer progression

“…Overall, independent groups have consistently reported opposite roles for TAp73 and DNp73, respectively, in repressing and promoting angiogenesis. Conversely, a fourth group identified a new E3 ubiquitin ligase, Siah1 (seven in absentia 1), that is able to degrade TAp73 following its regulation by HIF-1a [32], adding a further level of complexity to the p73/HIF interaction. Intriguingly, however, a relevant proangiogenic HIF-1a effect seems to be mediated by TAp73, at least in E1-Ras transformed MEFs.…”

Amino-terminal p53 mutations lead to expression of apoptosis proficient p47 and prognosticate better survival, but predispose to tumorigenesis

“…In essence, clinical samples obtained with SingHealth Centralized Institutional Review Board B ethics approval were used for p53EII transcript analyses and determination of p53 mutation status by standard sequencing and PCR, and also for immunoblot and immunohistochemical analyses, as described in detailed in SI Appendix. All cell culture and biochemical work, transfections, target gene analysis by quantitative real-time PCR, and chromatin immunoprecipitations were performed as described (28,38,39).…”

Eriocalyxin B, a natural diterpenoid, inhibited VEGF-induced angiogenesis and diminished angiogenesis-dependent breast tumor growth by suppressing VEGFR-2 signaling

“…Additionally, protein-protein interaction prediction showed that vascular endothelial growth factor receptor (VEGF-R) was altered, which may play a vital role in the regulation of SIV formation (Supporting Information, Figure S1F). Figure 2A showed the identified 72 different angiogenic genes with 21 up-regulated and 51 down-regulated after treatment with vehicle control (0.1% DMSO) or EriB (10 and 15 μM) for 72 h using a cut-off point (p < 0.05) and method described in the materials and methods section [28]. Results showed that the expressions of significantly altered genes (Fold-change > 2) were consistent with the alterations from transcriptome profiling validated by Real-time PCR (Figure 2B).…”

“…The differentially expressed genes were analyzed in the Database for Annotation, Visualization and Integrated Discovery (DAVID), which could identify the Gene Ontology (GO) terms and KEGG pathway maps. The angiogenesis related genes were identified according to GO enrichment analysis and Angiogenic Growth Factors RT 2 Profiler PCR Array (SABiosciences, Frederick, MD, USA) [28]. …”