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

Bieke Decaesteker (), Geertrui Denecker, Christophe Van Neste, Emmy M. Dolman, Wouter Van Loocke, Moritz Gartlgruber, Carolina Nunes, Fanny De Vloed, Pauline Depuydt, Karen Verboom, Dries Rombaut, Siebe Loontiens, Jolien De Wyn, Waleed M. Kholosy, Bianca Koopmans, Anke H. W. Essing, Carl Herrmann, Daniel Dreidax, Kaat Durinck, Dieter Deforce, Filip Nieuwerburgh, Anton Henssen, Rogier Versteeg, Valentina Boeva, Gudrun Schleiermacher, Johan van Nes, Pieter Mestdagh, Suzanne Vanhauwaert, Johannes H. Schulte, Frank Westermann, Jan J. Molenaar, Katleen De Preter and Frank Speleman ()
Additional contact information
Bieke Decaesteker: Center for Medical Genetics, Ghent University
Geertrui Denecker: Center for Medical Genetics, Ghent University
Christophe Van Neste: Center for Medical Genetics, Ghent University
Emmy M. Dolman: Princess Máxima Center for Pediatric Oncology, Department of Translational Research
Wouter Van Loocke: Center for Medical Genetics, Ghent University
Moritz Gartlgruber: Neuroblastoma Genomics, German Cancer Research Center (DKFZ)
Carolina Nunes: Center for Medical Genetics, Ghent University
Fanny De Vloed: Center for Medical Genetics, Ghent University
Pauline Depuydt: Center for Medical Genetics, Ghent University
Karen Verboom: Center for Medical Genetics, Ghent University
Dries Rombaut: Center for Medical Genetics, Ghent University
Siebe Loontiens: Center for Medical Genetics, Ghent University
Jolien De Wyn: Center for Medical Genetics, Ghent University
Waleed M. Kholosy: Princess Máxima Center for Pediatric Oncology, Department of Translational Research
Bianca Koopmans: Princess Máxima Center for Pediatric Oncology, Department of Translational Research
Anke H. W. Essing: Princess Máxima Center for Pediatric Oncology, Department of Translational Research
Carl Herrmann: University of Heidelberg
Daniel Dreidax: Neuroblastoma Genomics, German Cancer Research Center (DKFZ)
Kaat Durinck: Center for Medical Genetics, Ghent University
Dieter Deforce: Cancer Research Institute Ghent (CRIG)
Filip Nieuwerburgh: Cancer Research Institute Ghent (CRIG)
Anton Henssen: Charité-Universitätsmedizin Berlin
Rogier Versteeg: Academic Medical Center
Valentina Boeva: Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris Descartes University UMR-S1016
Gudrun Schleiermacher: Institut Curie, PSL Research University, Equipe Labellisée Ligue contre le Cancer, Laboratory Recherche Translationnelle en Oncologie Pédiatrique (RTOP), Laboratoire “Gilles Thomas”, Institut Curie, Department of Translational Research, Institut Curie, SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie
Johan van Nes: Academic Medical Center
Pieter Mestdagh: Center for Medical Genetics, Ghent University
Suzanne Vanhauwaert: Center for Medical Genetics, Ghent University
Johannes H. Schulte: Charité-Universitätsmedizin Berlin
Frank Westermann: Neuroblastoma Genomics, German Cancer Research Center (DKFZ)
Jan J. Molenaar: Princess Máxima Center for Pediatric Oncology, Department of Translational Research
Katleen De Preter: Center for Medical Genetics, Ghent University
Frank Speleman: Center for Medical Genetics, Ghent University

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (4)

Downloads: (external link)
https://www.nature.com/articles/s41467-018-06699-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06699-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-06699-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().