RT Journal Article
T1 Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions
A1 Martí, Juan Manuel
A1 Garcia-Diaz, Angel
A1 Delgado-Bellido, Daniel
A1 O'Valle, Francisco
A1 González-Flores, Ariannys
A1 Carlevaris, Onintza
A1 Rodríguez-Vargas, José Manuel
A1 Amé, Jean Christophe
A1 Dantzer, Françoise
A1 King, George L.
A1 Dziedzic, Klaudia
A1 Berra, Edurne
A1 de Álava, E.
A1 Amaral, A. T.
A1 Hammond, Ester M.
A1 Oliver, F. Javier
K1 Hypoxia
K1 PARP-1
K1 PARylation
K1 ChIP-seq
K1 Tumor microenvironment
K1 Hipoxia
K1 Inhibidores de poli(ADP-Ribosa) polimerasas
K1 Poli ADP ribosilación
K1 Secuenciación de inmunoprecipitación de cromatina
K1 Microambiente tumoral
AB 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
PB Elsevier
YR 2021
FD 2021-02-01
LK http://hdl.handle.net/10668/4345
UL http://hdl.handle.net/10668/4345
LA en
NO Martí JM, Garcia-Diaz A, Delgado-Bellido D, O'Valle F, González-Flores A, Carlevaris O, et al. Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions. Redox Biol. 2021 May;41:101885
DS RISalud
RD Apr 19, 2025