TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets
| Autor: | Dieter Deforce, Dries Rombaut, Karen Verboom, Jan J. Molenaar, Suzanne Vanhauwaert, Pieter Mestdagh, Johan van Nes, G Schleiermacher, Bieke Decaesteker, Johannes H. Schulte, Filip Van Nieuwerburgh, Franki Speleman, Christophe Van Neste, Rogier Versteeg, Jolien De Wyn, Carl Herrmann, Katleen De Preter, Geertrui Denecker, Moritz Gartlgruber, Kaat Durinck, Daniel Dreidax, Pauline Depuydt, Fanny De Vloed, Valentina Boeva, Wouter Van Loocke, Waleed M. Kholosy, Frank Westermann, Bianca Koopmans, Emmy Dolman, Anke H. W. Essing, Carolina de Carvalho Nunes, Siebe Loontiens, Anton G. Henssen |
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| Přispěvatelé: | Oncogenomics, CCA - Cancer biology and immunology, Human Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research General Physics and Astronomy Phenylenediamines BET-BROMODOMAIN INHIBITION Epigenesis Genetic Histones Neuroblastoma MYCN Panobinostat Medicine and Health Sciences Transcriptional regulation TUMOR-SUPPRESSOR lcsh:Science Epigenomics Regulation of gene expression Gene knockdown N-Myc Proto-Oncogene Protein Multidisciplinary Brain Neoplasms Kv Channel-Interacting Proteins Azepines CANCER Cyclin-Dependent Kinases Gene Expression Regulation Neoplastic Organoids TRANSCRIPTION FACTORS Signal Transduction EXPRESSION SEQUENCING DATA DNA Copy Number Variations Cell Survival Science Antineoplastic Agents Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Cell Line Tumor medicine Humans Transcription factor neoplasms CHROMOSOME ARM 17Q SET ENRICHMENT ANALYSIS HEK 293 cells Forkhead Box Protein M1 Biology and Life Sciences General Chemistry Triazoles medicine.disease GENE Repressor Proteins 030104 developmental biology HEK293 Cells Pyrimidines Cancer research FOXM1 lcsh:Q Tumor Suppressor Protein p53 T-Box Domain Proteins Cyclin-Dependent Kinase-Activating Kinase |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-17 (2018) Nature Communications Nature communications, 9(1). Nature Publishing Group NATURE COMMUNICATIONS |
| ISSN: | 2041-1723 |
| Popis: | Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors. In high-risk neuroblastoma cases, gains in chromosome 17q are common. Here, the authors investigate the epigenomics and transcriptomics of neuroblastoma, identifying TBX2 as a core regulatory circuitry component enhancing the reactivation of DREAM targets by MYCN/FOXM1. |
| Databáze: | OpenAIRE |
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