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Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions
dc.contributor.author | Martí, Juan Manuel | |
dc.contributor.author | García Díaz, Ángel | |
dc.contributor.author | Delgado Bellido, Daniel | |
dc.contributor.author | O'Valle Ravassa, Francisco Javier | |
dc.contributor.author | González Flores, Ariannys | |
dc.contributor.author | Oliver Pozo, Francisco Javier | |
dc.date.accessioned | 2021-06-14T06:52:08Z | |
dc.date.available | 2021-06-14T06:52:08Z | |
dc.date.issued | 2021-02-01 | |
dc.identifier.citation | Juan Manuel Martí, Angel Garcia-Diaz, Daniel Delgado-Bellido, Francisco O'Valle, Ariannys González-Flores, Onintza Carlevaris, José Manuel Rodríguez-Vargas, Jean Christophe Amé, Françoise Dantzer, George L. King, Klaudia Dziedzic, Edurne Berra, E. de Álava, A.T. Amaral, Ester M. Hammond, F. Javier Oliver, Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions, Redox Biology, Volume 41, 2021, 101885, ISSN 2213-2317, [https://doi.org/10.1016/j.redox.2021.101885] | es_ES |
dc.identifier.uri | http://hdl.handle.net/10481/69143 | |
dc.description | This work was supported by Junta de Andalucia, project of Excellence from Junta de Andalucia P10-CTS-0662, P12-CTS-383 to FJO, Spanish Ministry of Economy and Competitiveness SAF2012-40011C02-01, SAF2015-70520-R, RTI2018-098968-B-I00, RTICC RD12/0036/0026 and CIBER Cancer ISCIII CB16/12/00421 to FJO. EB1s lab is supported by the Basque Department of Industry, Tourism and Trade (Etortek) and the MINECO (CB16/12/00421) grants. Fundacion Domingo Martinez (call 2019). | es_ES |
dc.description | We would like to acknowledge Laura L´opez for technical assistance; Eduardo Andr´es and Laura Terr´on (Bioinformatic core IPBLN, CSIC) and Pan Hui (Bioinformatic Core, Joslin Diabetes center, Harvard Medical School). | es_ES |
dc.description.abstract | Background: The adaptation to hypoxia is mainly controlled by the HIF transcription factors. Increased expression/ activity of HIF-1α correlates with poor prognosis in cancer patients. PARP-1 inhibitors are used in the clinic to treat BRCAness breast/ovarian cancer and have been shown to regulate the hypoxic response; therefore, their use could be expanded. Methods: In this work by integrating molecular/cell biology approaches, genome-wide ChIP-seq, and patient samples, we elucidate the extent to which PARP-1 exerts control over HIF-1-regulated genes. Results: In human melanoma, PARP-1 and HIF-1α expression are strongly associated. In response to a hypoxic challenge poly(ADP-ribose) (PAR) is synthesized, HIF-1α is post-transcriptionally modified (PTM) and stabilized by PARylation at specific K/R residues located at its C-terminus. Using an unbiased ChIP-seq approach we demonstrate that PARP-1 dictates hypoxia-dependent HIF-recruitment to chromatin in a range of HIF-regulated genes while analysis of HIF-binding motifs (RCGTG) reveals a restriction on the recognition of hypoxia responsive elements in the absence of PARP-1. Consequently, the cells are poorly adapted to hypoxia, showing a reduced fitness during hypoxic induction. Conclusions: These data characterize the fine-tuning regulation by PARP-1/PARylation of HIF activation and suggest that PARP inhibitors might have therapeutic potential against cancer types displaying HIF-1α overactivation. | es_ES |
dc.description.sponsorship | Junta de Andalucia P10-CTS-0662 P12-CTS-38 | es_ES |
dc.description.sponsorship | Spanish Ministry of Economy and Competitiveness SAF2012-40011-C02-01 SAF2015-70520- R RTI2018-098968-B-I00 RTICC RD12/0036/0026 | es_ES |
dc.description.sponsorship | CIBER Cancer ISCIII CB16/12/00421 | es_ES |
dc.description.sponsorship | Basque Department of Industry, Tourism and Trade (Etortek) | es_ES |
dc.description.sponsorship | MINECO CB16/12/00421 | es_ES |
dc.description.sponsorship | Fundacion Domingo Martinez | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.rights | Atribución-NoComercial-SinDerivadas 3.0 España | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ | * |
dc.subject | Hypoxia | es_ES |
dc.subject | PARP-1 | es_ES |
dc.subject | PARylation | es_ES |
dc.subject | ChIP-seq | es_ES |
dc.subject | Tumor microenvironment | es_ES |
dc.title | Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es_ES |
dc.identifier.doi | 10.1016/j.redox.2021.101885 | |
dc.type.hasVersion | info:eu-repo/semantics/publishedVersion | es_ES |