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

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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.
Keywords
BET-BROMODOMAIN INHIBITION, SET ENRICHMENT ANALYSIS, CHROMOSOME ARM 17Q, TRANSCRIPTION FACTORS, TUMOR-SUPPRESSOR, SEQUENCING DATA, MYCN, CANCER, GENE, EXPRESSION

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Chicago
Decaesteker, Bieke, Geertrui Denecker, Christophe Van Neste, Emmy M Dolman, Wouter Van Loocke, Moritz Gartlgruber, Carolina de Carvalho Nunes, et al. 2018. “TBX2 Is a Neuroblastoma Core Regulatory Circuitry Component Enhancing MYCN/FOXM1 Reactivation of DREAM Targets.” Nature Communications 9.
APA
Decaesteker, B., Denecker, G., Van Neste, C., Dolman, E. M., Van Loocke, W., Gartlgruber, M., de Carvalho Nunes, C., et al. (2018). TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets. NATURE COMMUNICATIONS, 9.
Vancouver
1.
Decaesteker B, Denecker G, Van Neste C, Dolman EM, Van Loocke W, Gartlgruber M, et al. TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets. NATURE COMMUNICATIONS. 2018;9.
MLA
Decaesteker, Bieke, Geertrui Denecker, Christophe Van Neste, et al. “TBX2 Is a Neuroblastoma Core Regulatory Circuitry Component Enhancing MYCN/FOXM1 Reactivation of DREAM Targets.” NATURE COMMUNICATIONS 9 (2018): n. pag. Print.
@article{8581611,
  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.},
  articleno    = {4866},
  author       = {Decaesteker, Bieke and Denecker, Geertrui and Van Neste, Christophe and Dolman, Emmy M and Van Loocke, Wouter and Gartlgruber, Moritz and de Carvalho Nunes, Carolina and De Vloed, Fanny and Depuydt, Pauline and Verboom, Karen and Rombaut, Dries and Loontiens, Siebe and De Wyn, Jolien and Kholosy, Waleed M and Koopmans, Bianca and Essing, Anke HW and Herrmann, Carl and Dreidax, Daniel and Durinck, Kaat and Deforce, Dieter and Van Nieuwerburgh, Filip and Henssen, Anton and Versteeg, Rogier and Boeva, Valentina and Schleiermacher, Gudrun and van Nes, Johan and Mestdagh, Pieter and Vanhauwaert, Suzanne and Schulte, Johannes H and Westermann, Frank and Molenaar, Jan J and De Preter, Katleen and Speleman, Franki},
  issn         = {2041-1723},
  journal      = {NATURE COMMUNICATIONS},
  language     = {eng},
  pages        = {17},
  title        = {TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets},
  url          = {http://dx.doi.org/10.1038/s41467-018-06699-9},
  volume       = {9},
  year         = {2018},
}

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