AP-1 Signaling by Fra-1 Directly Regulates HMGA1 Oncogene Transcription in Triple-Negative Breast Cancers
| Autor: | Gabriel Moquet-Torcy, Thierry Gostan, Muhammad Ahmad Maqbool, Emilie Evanno, Olivier Kirsh, Fabienne Bejjani, Isabelle Jariel-Encontre, Claire Tolza, Marc Piechaczyk, Samantha Mahfoud |
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| Přispěvatelé: | Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM) |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Transcription Genetic [SDV]Life Sciences [q-bio] RNA polymerase II [SDV.CAN]Life Sciences [q-bio]/Cancer Triple Negative Breast Neoplasms HMGA1 Gene Chromosome conformation capture 03 medical and health sciences 0302 clinical medicine [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Cell Line Tumor Humans HMGA1a Protein Enhancer Molecular Biology Transcription factor ComputingMilieux_MISCELLANEOUS biology Promoter [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Oncogenes Chromatin Transcription Factor AP-1 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Cancer research Female Chromatin immunoprecipitation |
| Zdroj: | Molecular Cancer Research Molecular Cancer Research, American Association for Cancer Research, 2019, 17 (10), pp.1999-2014. ⟨10.1158/1541-7786.MCR-19-0036⟩ |
| ISSN: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1541-7786.MCR-19-0036⟩ |
| Popis: | The architectural chromatin protein HMGA1 and the transcription factor Fra-1 are both overexpressed in aggressive triple-negative breast cancers (TNBC), where they both favor epithelial-to-mesenchymal transition, invasion, and metastasis. We therefore explored the possibility that Fra-1 might be involved in enhanced transcription of the HMGA1 gene in TNBCs by exploiting cancer transcriptome datasets and resorting to functional studies combining RNA interference, mRNA and transcriptional run-on assays, chromatin immunoprecipitation, and chromosome conformation capture approaches in TNBC model cell lines. Our bioinformatic analysis indicated that Fra-1 and HMGA1 expressions positively correlate in primary samples of patients with TNBC. Our functional studies showed that Fra-1 regulates HMGA1 mRNA expression at the transcriptional level via binding to enhancer elements located in the last two introns of the gene. Although Fra-1 binding is required for p300/CBP recruitment at the enhancer domain, this recruitment did not appear essential for Fra-1–stimulated HMGA1 gene expression. Strikingly, Fra-1 binding is required for efficient recruitment of RNA Polymerase II at the HMGA1 promoter. This is permitted owing to chromatin interactions bringing about the intragenic Fra-1–binding enhancers and the gene promoter region. Fra-1 is, however, not instrumental for chromatin loop formation at the HMGA1 locus but rather exerts its transcriptional activity by exploiting chromatin interactions preexisting to its binding. Implications: We demonstrate that Fra-1 bound to an intragenic enhancer region is required for RNA Pol II recruitement at the HMGA1 promoter. Thereby, we provide novel insights into the mechanisms whereby Fra-1 exerts its prooncogenic transcriptional actions in the TNBC pathologic context. |
| Databáze: | OpenAIRE |
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