Artículo
Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions
Autor/es | Martí, Juan Manuel
Garcia-Diaz, Angel Delgado-Bellido, Daniel O'Valle, Francisco González-Flores, Ariannys Carlevaris, Onintza Álava Casado, Enrique de Oliver, F. Javier |
Departamento | Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica |
Fecha de publicación | 2021 |
Fecha de depósito | 2022-09-23 |
Publicado en |
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Resumen | 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 ... 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. |
Identificador del proyecto | P10-CTS-0662
P12-CTS-383 SAF2012-40011- C02-01 SAF2015-70520- R RTI2018-098968-B-I00 RTICC RD12/ 0036/0026 |
Cita | Martí, J.M., Garcia-Diaz, A., Delgado-Bellido, D., O'Valle, F., González-Flores, A., Carlevaris, O.,...,Oliver, F.J. (2021). Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions. Redox Biology, 41 |
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