Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
Nat Commun. 2018 Nov 19;9(1):4866. doi: 10.1038/s41467-018-06699-9.
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.
17 号染色体获得在高危神经母细胞瘤病例中几乎总是存在。在这里，我们通过 H3K27ac 定义的超级增强子对 17q 上的剂量敏感转录因子进行综合表观基因组学搜索，并确定 TBX2 为顶级候选基因。我们表明，TBX2 是神经母细胞瘤中最近建立的核心调控回路的组成部分，具有细胞身份转录因子的特征，通过激活 p21-DREAM 抑制的 FOXM1 靶基因来驱动增殖。MYCN/TBX2 联合敲低可促进细胞生长停滞，表明 TBX2 增强了 MYCN 对 FOXM1 靶基因的持续激活。联合 CDK7 和 BET 溴结构域抑制剂靶向转录成瘾性对细胞活力具有协同作用，对 CRC 基因表达和 p53 通路反应以及几个涉及转录调节的基因具有强烈的抑制作用。总之，我们深入了解了 TBX2 CRC 基因在神经母细胞瘤细胞转录依赖性中的作用，值得使用 BET 和 CDK7 抑制剂进行临床试验。
