PMID- 30381462 OWN - NLM STAT- MEDLINE DCOM- 20190123 LR - 20210109 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 115 IP - 46 DP - 2018 Nov 13 TI - p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression. PG - E10869-E10878 LID - 10.1073/pnas.1808314115 [doi] AB - 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-gamma2, 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. CI - Copyright (c) 2018 the Author(s). Published by PNAS. FAU - Amelio, Ivano AU - Amelio I AD - Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom; ia348@mrc-tox.cam.ac.uk gm614@mrc-tox.cam.ac.uk. FAU - Mancini, Mara AU - Mancini M AUID- ORCID: 0000-0001-5173-4854 AD - Biochemistry Laboratory, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), 00167 Rome, Italy. FAU - Petrova, Varvara AU - Petrova V AD - Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom. FAU - Cairns, Rob A AU - Cairns RA AD - The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 2C1. FAU - Vikhreva, Polina AU - Vikhreva P AD - Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom. FAU - Nicolai, Sara AU - Nicolai S AD - Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom. FAU - Marini, Alberto AU - Marini A AD - Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom. FAU - Antonov, Alexey A AU - Antonov AA AD - Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom. FAU - Le Quesne, John AU - Le Quesne J AD - Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom. AD - Department of Cancer Studies, University of Leicester, LE1 9HN Leicester, United Kingdom. FAU - Baena Acevedo, Juvenal D AU - Baena Acevedo JD AD - Department of Genetics, University of Leicester, LE1 9HN Leicester, United Kingdom. FAU - Dudek, Kate AU - Dudek K AD - Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom. FAU - Sozzi, Gabriella AU - Sozzi G AD - Tumour Genomics, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, 20133 Milan, Italy. FAU - Pastorino, Ugo AU - Pastorino U AD - Thoracic Surgery, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, 20133 Milan, Italy. FAU - Knight, Richard A AU - Knight RA AD - Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom. FAU - Mak, Tak W AU - Mak TW AD - The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 2C1. FAU - Melino, Gerry AU - Melino G AUID- ORCID: 0000-0001-9428-5972 AD - Medical Research Council (MRC) Toxicology Unit, University of Cambridge, LE1 9HN Leicester, United Kingdom; ia348@mrc-tox.cam.ac.uk gm614@mrc-tox.cam.ac.uk. AD - Department of Experimental Medicine and Surgery, IDI-IRCCS, University of Rome Tor Vergata, 00133 Rome, Italy. LA - eng GR - MC_U132670600/MRC_/Medical Research Council/United Kingdom GR - MC_UP_1203/1/MRC_/Medical Research Council/United Kingdom GR - MC_UU_00025/2/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181031 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Hypoxia-Inducible Factor 1) RN - 0 (TP53 protein, human) RN - 0 (Tumor Suppressor Protein p53) SB - IM MH - Animals MH - Carcinoma, Non-Small-Cell Lung/*genetics/metabolism/pathology MH - Cell Hypoxia/genetics MH - Cell Line, Tumor MH - Extracellular Matrix MH - Genes, p53 MH - Heterografts MH - Humans MH - Hypoxia-Inducible Factor 1/*genetics/metabolism MH - Lung Neoplasms/*genetics/metabolism/pathology MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Mutation MH - Transcriptional Activation MH - Tumor Microenvironment MH - Tumor Suppressor Protein p53/genetics/*metabolism PMC - PMC6243248 OTO - NOTNLM OT - HIF OT - SWI/SNF OT - chromatin architecture OT - microenvironment OT - p53 COIS- The authors declare no conflict of interest. EDAT- 2018/11/02 06:00 MHDA- 2019/01/24 06:00 PMCR- 2018/10/31 CRDT- 2018/11/02 06:00 PHST- 2018/11/02 06:00 [pubmed] PHST- 2019/01/24 06:00 [medline] PHST- 2018/11/02 06:00 [entrez] PHST- 2018/10/31 00:00 [pmc-release] AID - 1808314115 [pii] AID - 201808314 [pii] AID - 10.1073/pnas.1808314115 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2018 Nov 13;115(46):E10869-E10878. doi: 10.1073/pnas.1808314115. Epub 2018 Oct 31.