Abstract
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.
Highlights
Triple-negative breast cancers (TNBC) constitute a highly aggressive tumor subtype with dismal prognosis
Our results showed that both Fra-1 and HMGA1 mRNAs (i) are globally higher in ER-negative (ERÀ) than in ER-positive (ERþ) breast cancers, and (ii) are the most abundant in the aggressive basal-like breast cancers (Fig. 1B, top and central), a subtype very similar to, but not completely overlapping, TNBCs [50]
Work by others has previously shown that the Fra-1 transcription factor and the chromatin-associated protein HMGA1 are both overexpressed in TNBCs, where they both contribute to tumorigenesis and metastasis with widely overlapping biological effects [4,5,6, 37, 41, 42]
Summary
Triple-negative breast cancers (TNBC) constitute a highly aggressive tumor subtype with dismal prognosis. TNBCs cannot benefit from any of the targeted therapies currently available for a number of other mammary tumors, as they neither express the. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Tolza: Centre de Recherche en Biologie Cellulaire de Montpellier, University of Montpellier, CNRS, Montpellier, France; current address for M.A. Maqbool, Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom; and current addresss for O. Universite de Paris, EDC, UMR7216, CNRS, Paris, France
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