Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions

• Published in: Redox biology Vol. 41; p. 101885
• Main Authors: Martí, Juan Manuel, Garcia-Diaz, Angel, Delgado-Bellido, Daniel, O'Valle, Francisco, González-Flores, Ariannys, Carlevaris, Onintza, Rodríguez-Vargas, José Manuel, Amé, Jean Christophe, Dantzer, Françoise, King, George L., Dziedzic, Klaudia, Berra, Edurne, de Álava, E., Amaral, A.T., Hammond, Ester M., Oliver, F. Javier
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2021; Elsevier
• Subjects: Biochemistry, Molecular Biology; Cancer; Cellular Biology; ChIP-seq; Genomics; Hypoxia; Life Sciences; PARP-1; PARylation; Research Paper; Subcellular Processes; Tumor microenvironment; ChIP-seq; Hypoxia; Tumor microenvironment; PARP-1; PARylation
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2021.101885

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. 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. 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. 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.