Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/44403
Title: p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression.
Authors: Amelio, I
Mancini, M
Petrova, V
Cairns, RA
Vikhreva, P
Nicolai, S
Marini, A
Antonov, AA
Le Quesne, J
Baena Acevedo, JD
Dudek, K
Sozzi, G
Pastorino, U
Knight, RA
Mak, TW
Melino, G
First Published: 13-Nov-2018
Publisher: National Academy of Sciences
Citation: Proceedings of the National Academy of Sciences, 2018, 115 (46), pp. E10869-E10878
Abstract: Mutations in the TP53 gene and microenvironmentally driven activation of hypoxia-inducible factor-1 (HIF-1) typically occur in later stages of tumorigenesis. An ongoing challenge is the identification of molecular determinants of advanced cancer pathogenesis to design alternative last-line therapeutic options. Here, we report that p53 mutants influence the tumor microenvironment by cooperating with HIF-1 to promote cancer progression. We demonstrate that in non-small cell lung cancer (NSCLC), p53 mutants exert a gain-of-function (GOF) effect on HIF-1, thus regulating a selective gene expression signature involved in protumorigenic functions. Hypoxia-mediated activation of HIF-1 leads to the formation of a p53 mutant/HIF-1 complex that physically binds the SWI/SNF chromatin remodeling complex, promoting expression of a selective subset of hypoxia-responsive genes. Depletion of p53 mutants impairs the HIF-mediated up-regulation of extracellular matrix (ECM) components, including type VIIa1 collagen and laminin-γ2, thus affecting tumorigenic potential of NSCLC cells in vitro and in mouse models in vivo. Analysis of surgically resected human NSCLC revealed that expression of this ECM gene signature was highly correlated with hypoxic tumors exclusively in patients carrying p53 mutations and was associated with poor prognosis. Our data reveal a GOF effect of p53 mutants in hypoxic tumors and suggest synergistic activities of p53 and HIF-1. These findings have important implications for cancer progression and might provide innovative last-line treatment options for advanced NSCLC.
DOI Link: 10.1073/pnas.1808314115
eISSN: 1091-6490
Links: https://www.pnas.org/content/115/46/E10869
http://hdl.handle.net/2381/44403
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2018. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Description: This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1808314115/-/DCSupplemental.
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine



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