title: 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.
authors.affiliation: Division of Cellular &Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore.
authors.forename: Iqbal
authors.initials: I
authors.lastname: Dulloo
authors.affiliation: Division of Cellular &Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore.
authors.forename: Beng Hooi
authors.initials: BH
authors.lastname: Phang
authors.affiliation: Division of Cellular &Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore.
authors.forename: Rashidah
authors.initials: R
authors.lastname: Othman
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore 169608, Singapore.
authors.forename: Soo Yong
authors.initials: SY
authors.lastname: Tan
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
authors.forename: Aadhitthya
authors.initials: A
authors.lastname: Vijayaraghavan
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
authors.forename: Liang Kee
authors.initials: LK
authors.lastname: Goh
authors.affiliation: Instituto de Biomedicina (IBIOMED), Campus Universitario, León 24071, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Martin-Lopez
authors.affiliation: Instituto de Biomedicina (IBIOMED), Campus Universitario, León 24071, Spain.
authors.forename: Margarita M
authors.initials: MM
authors.lastname: Marques
authors.affiliation: Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
authors.forename: Chun Wei
authors.initials: CW
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
authors.forename: De Yun
authors.initials: de Y
authors.lastname: Wang
authors.affiliation: Instituto de Biomedicina (IBIOMED), Campus Universitario, León 24071, Spain.
authors.forename: Maria Carmen
authors.initials: MC
authors.lastname: Marín
authors.affiliation: Institute of Medical Biology, A-STAR, Singapore 138672, Singapore.
authors.forename: Wa
authors.initials: W
authors.lastname: Xian
authors.affiliation: Genome Institute of Singapore, A-STAR, Singapore 138672, Singapore.
authors.forename: Frank
authors.initials: F
authors.lastname: McKeon
authors.affiliation: 1] Division of Cellular &Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore [2] Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore [3] Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
authors.forename: Kanaga
authors.initials: K
authors.lastname: Sabapathy
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000235:genetics; D054875:Ubiquitination; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D000098563:Seven in Absentia Proteins
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins