November 19, 2018
n 384-well plates and incubated overnight. Next, cell lines and organoids were co-treated with three-fold dilution series of JQ1 (5.1 nMâ33.3 ÎźM) and THZ1 (0.051 nMâ0.333 ÎźM), using the HP D300 Digital Dispenser (Tecan). Control cells were treated with DMSO. Cell viability was determined after 72 h (classical cell lines) or 120 h (organoids) using the 3-(4.5-dimethylthiazol-2-yl)
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.
Decaesteker, B; Denecker, G; Van Neste, C; Dolman, EM; Van Loocke, W; Gartlgruber, M; Nunes, C; De Vloed, F; Depuydt, P; Verboom, K; Rombaut, D; Loontiens, S; De Wyn, J; Kholosy, WM; Koopmans, B; Essing, AHW; Herrmann, C; Dreidax, D; Durinck, K; Deforce, D; Van Nieuwerburgh, F; Henssen, A; Versteeg, R; Boeva, V; Schleiermacher, G; van Nes, J; Mestdagh, P; Vanhauwaert, S; Schulte, JH; Westermann, F; Molenaar, JJ; De Preter, K; Speleman, F;
Journal: Nat Commun Pages: 4866