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

Author

Listed:
  • Bieke Decaesteker

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Geertrui Denecker

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Christophe Van Neste

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Emmy M. Dolman

    (Princess Máxima Center for Pediatric Oncology, Department of Translational Research)

  • Wouter Van Loocke

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Moritz Gartlgruber

    (Neuroblastoma Genomics, German Cancer Research Center (DKFZ))

  • Carolina Nunes

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Fanny De Vloed

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Pauline Depuydt

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Karen Verboom

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Dries Rombaut

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Siebe Loontiens

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Jolien De Wyn

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • 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
    German Cancer Research Center (DKFZ))

  • Daniel Dreidax

    (Neuroblastoma Genomics, German Cancer Research Center (DKFZ))

  • Kaat Durinck

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Dieter Deforce

    (Cancer Research Institute Ghent (CRIG)
    Ghent University)

  • Filip Nieuwerburgh

    (Cancer Research Institute Ghent (CRIG)
    Ghent University)

  • Anton Henssen

    (Charité-Universitätsmedizin Berlin
    German Cancer Consortium (DKTK)
    Berlin Institute of Health)

  • 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
    Cancer Research Institute Ghent (CRIG))

  • Suzanne Vanhauwaert

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

  • 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
    Cancer Research Institute Ghent (CRIG))

  • Frank Speleman

    (Center for Medical Genetics, Ghent University
    Cancer Research Institute Ghent (CRIG))

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.

Suggested Citation

  • 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 Romba, 2018. "TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06699-9
    DOI: 10.1038/s41467-018-06699-9
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    Cited by:

    1. Bieke Decaesteker & Amber Louwagie & Siebe Loontiens & Fanny De Vloed & Sarah-Lee Bekaert & Juliette Roels & Suzanne Vanhauwaert & Sara De Brouwer & Ellen Sanders & Alla Berezovskaya & Geertrui Deneck, 2023. "SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Cécile Thirant & Agathe Peltier & Simon Durand & Amira Kramdi & Caroline Louis-Brennetot & Cécile Pierre-Eugène & Margot Gautier & Ana Costa & Amandine Grelier & Sakina Zaïdi & Nadège Gruel & Irène Ji, 2023. "Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Shigekazu Murakami & Shannon M. White & Alec T. McIntosh & Chan D. K. Nguyen & Chunling Yi, 2023. "Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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