AP-1 Signaling by Fra-1 Directly Regulates HMGA1 Oncogene Transcription in Triple-Negative Breast Cancers

• Published in: Molecular cancer research Vol. 17; no. 10; pp. 1999 - 2014
• Main Authors: Tolza, Claire, Bejjani, Fabienne, Evanno, Emilie, Mahfoud, Samantha, Moquet-Torcy, Gabriel, Gostan, Thierry, Maqbool, Muhammad Ahmad, Kirsh, Olivier, Piechaczyk, Marc, Jariel-Encontre, Isabelle
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.10.2019
• Subjects: Biochemistry, Molecular Biology; Cancer; Genomics; Life Sciences; Molecular biology
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-19-0036

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 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 gene expression. Strikingly, Fra-1 binding is required for efficient recruitment of RNA Polymerase II at the 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 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 promoter. Thereby, we provide novel insights into the mechanisms whereby Fra-1 exerts its prooncogenic transcriptional actions in the TNBC pathologic context.