2. Academic Validation
  3. TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets

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

  • Nat Commun. 2018 Nov 19;9(1):4866. doi: 10.1038/s41467-018-06699-9.
Bieke Decaesteker 1 2,  Geertrui Denecker 3 4,  Christophe Van Neste 3 4,  Emmy M Dolman 5,  Wouter Van Loocke 3 4,  Moritz Gartlgruber 6,  Carolina Nunes 3 4,  Fanny De Vloed 3 4,  Pauline Depuydt 3 4,  Karen Verboom 3 4,  Dries Rombaut 3 4,  Siebe Loontiens 3 4,  Jolien De Wyn 3 4,  Waleed M Kholosy 5,  Bianca Koopmans 5,  Anke H W Essing 5,  Carl Herrmann 7 8,  Daniel Dreidax 6,  Kaat Durinck 3 4,  Dieter Deforce 4 9,  Filip Van Nieuwerburgh 4 9,  Anton Henssen 10 11 12,  Rogier Versteeg 13,  Valentina Boeva 14,  Gudrun Schleiermacher 15,  Johan van Nes 13,  Pieter Mestdagh 3 4,  Suzanne Vanhauwaert 3 4,  Johannes H Schulte 10,  Frank Westermann 6,  Jan J Molenaar 5,  Katleen De Preter 3 4,  Frank Speleman 16 17
Affiliations

Affiliations

  • 1 Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium. [email protected].
  • 2 Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium. [email protected].
  • 3 Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
  • 4 Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
  • 5 Princess Máxima Center for Pediatric Oncology, Department of Translational Research, Utrecht, 3584, The Netherlands.
  • 6 Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
  • 7 Institute of Pharmacy and Molecular Biotechnology, and Bioquant Center, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg, 69120, Germany.
  • 8 Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
  • 9 Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, 9000, Belgium.
  • 10 Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, 13353, Germany.
  • 11 German Cancer Consortium (DKTK), Heidelberg, 69120, Germany.
  • 12 Berlin Institute of Health, Berlin, 13353, Germany.
  • 13 Department of Oncogenomics, Academic Medical Center, Amsterdam, 1105, AZ, Netherlands.
  • 14 Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris Descartes University UMR-S1016, Paris, 75014, France.
  • 15 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, Paris, 75248, France.
  • 16 Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium. [email protected].
  • 17 Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium. [email protected].
PMID: 30451831 DOI: 10.1038/s41467-018-06699-9
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.

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