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TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets

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Item Type:Article
Title:TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets
Creators Name:Decaesteker, B. and Denecker, G. and Van Neste, C. and Dolman, E.M. and Van Loocke, W. and Gartlgruber, M. and Nunes, C. and De Vloed, F. and Depuydt, P. and Verboom, K. and Rombaut, D. and Loontiens, S. and De Wyn, J. and Kholosy, W.M. and Koopmans, B. and Essing, A.H.W. and Herrmann, C. and Dreidax, D. and Durinck, K. and Deforce, D. and van Nieuwerburgh, F. and Henssen, A. and Versteeg, R. and Boeva, V. and Schleiermacher, G. and van Nes, J. and Mestdagh, P. and Vanhauwaert, S. and Schulte, J.H. and Westermann, F. and Molenaar, J.J. and De Preter, K. and Speleman, F.
Abstract: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.
Keywords:Antineoplastic Agents, Azepines, Brain Neoplasms, Cell Survival, Cyclin-Dependent Kinases, DNA Copy Number Variations, Genetic Epigenesis, Forkhead Box Protein M1, HEK293 Cells, Histones, Kv Channel-Interacting Proteins, N-Myc Proto-Oncogene Protein, Neoplastic Gene Expression Regulation, Neuroblastoma, Organoids, Panobinostat, Phenylenediamines, Pyrimidines, Repressor Proteins, Signal Transduction, T-Box Domain Proteins, Triazoles, Tumor Cell Line, Tumor Suppressor Protein p53
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
Volume:9
Number:1
Page Range:4866
Date:19 November 2018
Official Publication:https://doi.org/10.1038/s41467-018-06699-9
PubMed:View item in PubMed

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