TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Decaesteker, Bieke; Denecker, Geertrui; Van Neste, Christophe; Dolman, Emmy; Van Loocke, Wouter; Gartlgruber, Moritz; Nunes, Carolina; De Vloed, Fanny; Depuydt, Pauline; Verboom, Karen; Rombaut, Dries; Loontiens, Siebe; De Wyn, Jolien; Kholosy, Waleed; Koopmans, Bianca; Essing, Anke; Herrmann, Carl; Dreidax, Daniel; Durinck, Kaat; Deforce, Dieter; Nieuwerburgh, Filip; Henssen, Anton; Versteeg, Rogier; Boeva, Valentina; Schleiermacher, Gudrun; van Nes, Johan; Mestdagh, Pieter; Vanhauwaert, Suzanne; Schulte, Johannes; Westermann, Frank; Molenaar, Jan; De Preter, Katleen; Speleman, Frank;
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 17
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-06699-9
• Languages: English
• ISSNs: 2041-1723

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 identifyTBX2 as top candidate gene. We show thatTBX2 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. CombinedMYCN/TBX2 knockdown enforces cell growth arrest suggesting thatTBX2 enhancesMYCN 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 theTBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors. In high-risk neuroblastoma cases, gains in chromosome 17q are common. Here, the authors investigate the epigenomics and transcriptomics of neuroblastoma, identifying TBX2 as a core regulatory circuitry component enhancing the reactivation of DREAM targets by MYCN/FOXM1.