%0 Journal Article
%A Martí, Juan Manuel
%A Garcia-Diaz, Angel
%A Delgado-Bellido, Daniel
%A O'Valle, Francisco
%A González-Flores, Ariannys
%A Carlevaris, Onintza
%A Rodríguez-Vargas, José Manuel
%A Amé, Jean Christophe
%A Dantzer, Françoise
%A King, George L.
%A Dziedzic, Klaudia
%A Berra, Edurne
%A de Álava, E.
%A Amaral, A. T.
%A Hammond, Ester M.
%A Oliver, F. Javier
%T Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions
%D 2021
%U http://hdl.handle.net/10668/4345
%X Background: The adaptation to hypoxia is mainly controlled by the HIF transcription factors. Increased expres sion/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 over activation
%K Hypoxia
%K PARP-1
%K PARylation
%K ChIP-seq
%K Tumor microenvironment
%K Hipoxia
%K Inhibidores de poli(ADP-Ribosa) polimerasas
%K Poli ADP ribosilación
%K Secuenciación de inmunoprecipitación de cromatina
%K Microambiente tumoral
%~