Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions
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AuthorMartí, Juan Manuel; García Díaz, Ángel; Delgado Bellido, Daniel; O'Valle Ravassa, Francisco Javier; González Flores, Ariannys; Oliver Pozo, Francisco Javier
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]
SponsorshipJunta de Andalucia P10-CTS-0662 P12-CTS-38; Spanish Ministry of Economy and Competitiveness SAF2012-40011-C02-01 SAF2015-70520- R RTI2018-098968-B-I00 RTICC RD12/0036/0026; CIBER Cancer ISCIII CB16/12/00421; Basque Department of Industry, Tourism and Trade (Etortek); MINECO CB16/12/00421; Fundacion Domingo Martinez
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.