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
MetadataShow full item record
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
- Fra-1 regulates its target genes via binding to remote enhancers without exerting major control on chromatin architecture in triple negative breast cancers.
- Authors: Bejjani F, Tolza C, Boulanger M, Downes D, Romero R, Maqbool MA, Zine El Aabidine A, Andrau JC, Lebre S, Brehelin L, Parrinello H, Rohmer M, Kaoma T, Vallar L, Hughes JR, Zibara K, Lecellier CH, Piechaczyk M, Jariel-Encontre I
- Issue date: 2021 Mar 18
- HMGA1 promotes breast cancer angiogenesis supporting the stability, nuclear localization and transcriptional activity of FOXM1.
- Authors: Zanin R, Pegoraro S, Ros G, Ciani Y, Piazza S, Bossi F, Bulla R, Zennaro C, Tonon F, Lazarevic D, Stupka E, Sgarra R, Manfioletti G
- Issue date: 2019 Jul 16
- Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer.
- Authors: Zhao C, Qiao Y, Jonsson P, Wang J, Xu L, Rouhi P, Sinha I, Cao Y, Williams C, Dahlman-Wright K
- Issue date: 2014 Jul 15
- Fra-1 Regulates the Expression of HMGA1, Which is Associated with a Poor Prognosis in Human Esophageal Squamous Cell Carcinoma.
- Authors: Toyozumi T, Hoshino I, Takahashi M, Usui A, Akutsu Y, Hanari N, Murakami K, Kano M, Akanuma N, Suitoh H, Matsumoto Y, Sekino N, Komatsu A, Matsubara H
- Issue date: 2017 Oct
- AP-1-mediated chromatin looping regulates ZEB2 transcription: new insights into TNFα-induced epithelial-mesenchymal transition in triple-negative breast cancer.
- Authors: Qiao Y, Shiue CN, Zhu J, Zhuang T, Jonsson P, Wright AP, Zhao C, Dahlman-Wright K
- Issue date: 2015 Apr 10