Children's Cancer Institute Australia, Randwick Sydney, NSW, 2031, Australia.
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Nat Commun. 2019 Jul 25;10(1):3319. doi: 10.1038/s41467-019-11132-w.
Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. The JMJD6 gene at 17q21-ter activates gene transcription. Here we show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice, and high levels of JMJD6 expression in human neuroblastoma tissues independently predict poor patient prognosis. In addition, JMJD6 gene is associated with transcriptional super-enhancers. Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression. Our findings therefore identify JMJD6 as a neuroblastoma tumorigenesis factor, and the combination therapy as a treatment strategy.
17q21 端的染色体常发生在神经母细胞瘤中，但该区域中哪个基因对肿瘤发生很重要尚不清楚。17q21 端的 JMJD6 基因激活基因转录。我们在此表明，JMJD6 与 N-Myc 和 BRD4 形成蛋白复合物，并对 E2F2、N-Myc 和 c-Myc 的转录很重要。敲低 JMJD6 可减少体外神经母细胞瘤细胞的增殖和存活以及在小鼠中的肿瘤进展，并且人神经母细胞瘤组织中 JMJD6 表达水平高可独立预测患者预后不良。此外，JMJD6 基因与转录超级增强子相关。CDK7/超级增强子抑制剂 THZ1 和组蛋白去乙酰化酶抑制剂 panobinostat 的联合治疗可协同降低 JMJD6、E2F2、N-Myc、c-Myc 的表达，在体外诱导细胞凋亡，并导致小鼠神经母细胞瘤肿瘤消退，而强制过表达 JMJD6 则显著逆转了这些作用。因此，我们的研究结果确定 JMJD6 为神经母细胞瘤肿瘤发生因子，联合治疗为治疗策略。
