Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions
BACKGROUND:<br> 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 s...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Elsevier
2021
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| _version_ | 1797097301213184000 |
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| author | Martí, JM Garcia-Diaz, A Delgado-Bellido, D O'Valle, F González-Flores, A Carlevaris, O Rodríguez-Vargas, JM Amé, JC Dantzer, F King, GL Dziedzic, K Berra, E de Álava, E Amaral, AT Hammond, E Oliver, FJ |
| author_facet | Martí, JM Garcia-Diaz, A Delgado-Bellido, D O'Valle, F González-Flores, A Carlevaris, O Rodríguez-Vargas, JM Amé, JC Dantzer, F King, GL Dziedzic, K Berra, E de Álava, E Amaral, AT Hammond, E Oliver, FJ |
| author_sort | Martí, JM |
| collection | OXFORD |
| description | BACKGROUND:<br> 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. <br>METHODS: <br>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.<br> RESULTS:<br> 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. <br>CONCLUSIONS: <br>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. |
| first_indexed | 2024-03-07T04:53:34Z |
| format | Journal article |
| id | oxford-uuid:d5cc1da5-46f5-4aa8-8669-860f1a8ab43f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:53:34Z |
| publishDate | 2021 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:d5cc1da5-46f5-4aa8-8669-860f1a8ab43f2022-03-27T08:28:44ZSelective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditionsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d5cc1da5-46f5-4aa8-8669-860f1a8ab43fEnglishSymplectic ElementsElsevier2021Martí, JMGarcia-Diaz, ADelgado-Bellido, DO'Valle, FGonzález-Flores, ACarlevaris, ORodríguez-Vargas, JMAmé, JCDantzer, FKing, GLDziedzic, KBerra, Ede Álava, EAmaral, ATHammond, EOliver, FJBACKGROUND:<br> 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. <br>METHODS: <br>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.<br> RESULTS:<br> 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. <br>CONCLUSIONS: <br>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. |
| spellingShingle | Martí, JM Garcia-Diaz, A Delgado-Bellido, D O'Valle, F González-Flores, A Carlevaris, O Rodríguez-Vargas, JM Amé, JC Dantzer, F King, GL Dziedzic, K Berra, E de Álava, E Amaral, AT Hammond, E Oliver, FJ Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions |
| title | Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions |
| title_full | Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions |
| title_fullStr | Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions |
| title_full_unstemmed | Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions |
| title_short | Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions |
| title_sort | 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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