AP-1 signaling by Fra-1 directly regulates HMGA1 oncogene transcription in triple negative breast cancers
AffiliationInstitut de Genetique Moleculaire de Montpellier, CNRS, University of Montpellier
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AbstractThe architectural chromatin protein HMGA1 and the transcription factor Fra-1 are both overexpressed in aggressive Triple Negative Breast Cancers (TNBCs), 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 data sets 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 TNBC patients. 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 pro-oncogenic transcriptional actions in the TNBC pathological context.
CitationTolza C, Bejjani F, Evanno E, Mahfoud S, Moquet-Torcy G, Gostan T, et al. AP-1 signaling by Fra-1 directly regulates HMGA1 oncogene transcription in triple negative breast cancers. Mol Cancer Res. 2019 Jul 12.
JournalMolecular Cancer Research