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  • 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

1 déc. 2018Nature Communications

DOI : 10.1038/s41467-018-06699-9

Auteurs

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 Van 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, Frank Speleman

Résumé

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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