Hypoxia-inducible TAp73 supports tumorigenesis by regulating the angiogenic transcriptome

Nature Cell Biology
Iqbal DullooKanaga Sabapathy

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.

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Citations

Nov 19, 2015·Proceedings of the National Academy of Sciences of the United States of America·Beng Hooi PhangKanaga Sabapathy
Apr 14, 2016·Cellular Immunology·Wei DengLingyun Sun
Jun 3, 2015·Trends in Biochemical Sciences·Ivano Amelio, Gerry Melino
Dec 14, 2017·Cell Cycle·Ningxia XieGerry Melino
Dec 30, 2015·Molecular and Cellular Biology·Kanaga Sabapathy
Feb 5, 2019·Journal of Cellular Biochemistry·Kamia Tanwar, Uttam Pati
Feb 12, 2020·Scientific Reports·Shashipavan ChillappagariM Lienhard Schmitz
Feb 13, 2018·Experimental and Therapeutic Medicine·Zhi-Peng JiJian-Liang Zhang
Jul 31, 2018·Signal Transduction and Targeted Therapy·Dan LiKanaga Sabapathy
Aug 15, 2020·Signal Transduction and Targeted Therapy·Jie ChenQimin Zhan
Mar 20, 2018·Oncology Letters·Meng WuWeiping Wang
Oct 5, 2019·Journal of Cell Science·Alice Nemajerova, Ute M Moll
Feb 23, 2020·International Journal of Molecular Sciences·Chao WangKanaga Sabapathy
Feb 13, 2019·Free Radical Biology & Medicine·Aimeric CabriéMichel Lepoivre
Aug 10, 2021·Frontiers in Cell and Developmental Biology·Laura Maeso-AlonsoMaria C Marin

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