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

Abstract

<div>Abstract<p>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 <i>HMGA1</i> 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 <i>HMGA1</i> gene expression. Strikingly, Fra-1 binding is required for efficient recruitment of RNA Polymerase II at the <i>HMGA1</i> 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 <i>HMGA1</i> locus but rather exerts its transcriptional activity by exploiting chromatin interactions preexisting to its binding.</p>Implications:<p>We demonstrate that Fra-1 bound to an intragenic enhancer region is required for RNA Pol II recruitement at the <i>HMGA1</i> promoter. Thereby, we provide novel insights into the mechanisms whereby Fra-1 exerts its prooncogenic transcriptional actions in the TNBC pathologic context.</p></div>