Collaborative ISL1/GATA3 interaction in controlling neuroblastoma oncogenic pathways overlapping with but distinct from MYCN
Collaborative ISL1/GATA3 interaction in controlling neuroblastoma oncogenic pathways overlapping with but distinct from MYCN
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DOI：
10.7150/thno.30199
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发表时间：
2019-01
期刊：
影响因子：
12.4
通讯作者：
Qitong Zhang;Qingquan Zhang;Xue Jiang;Youqiong Ye;Huimin Liao;Fugui Zhu;Jie Yan;Lina Luo
中科院分区：
文献类型：
--
作者：
Qitong Zhang;Qingquan Zhang;Xue Jiang;Youqiong Ye;Huimin Liao;Fugui Zhu;Jie Yan;Lina Luo
背景：转录因子ISL 1在交感神经发生中起关键作用。ISL 1的表达与神经母细胞瘤（一种源自交感-肾上腺祖细胞的儿科肿瘤）相关，然而ISL 1在神经母细胞瘤中的作用尚未探索。方法：在这里，我们敲低SH-SY 5 Y神经母细胞瘤细胞中的ISL 1（KD），并进行RNA-seq和ISL 1 ChIP-seq分析。结果如下：对这些数据的分析表明，ISL 1在神经母细胞瘤增殖和分化所必需的多个致癌基因和途径的上游起作用，包括LMO 1和LIN 28 B。ISL 1促进许多细胞周期相关基因的表达，但抑制分化相关基因，包括RA受体和下游靶基因EPAS 1和CDKN 1A。因此，ISL 1的敲低在体外抑制神经母细胞瘤细胞增殖和迁移，在体内阻碍肿瘤生长，并通过RA治疗增强神经元分化。此外，全基因组定位揭示了ISL 1和GATA 3的结合区域的大量共占据，并且ISL 1与GATA 3物理相互作用，并且它们一起协同调节上述致癌途径。此外，对ISL 1和MYCN在MYCN扩增和MYCN非扩增神经母细胞瘤细胞中的作用的分析揭示了ISL 1和MYCN之间的上位关系。ISL 1和MYCN在神经母细胞瘤中平行发挥作用，调节共同但不同的致癌途径。结论：我们的研究表明，ISL 1在神经母细胞瘤调控网络中起着重要作用，并可能成为神经母细胞瘤的潜在治疗靶点。
Background: Transcription factor ISL1 plays a critical role in sympathetic neurogenesis. Expression of ISL1 has been associated with neuroblastoma, a pediatric tumor derived from sympatho-adrenal progenitors, however the role of ISL1 in neuroblastoma remains unexplored. Method: Here, we knocked down ISL1 (KD) in SH-SY5Y neuroblastoma cells and performed RNA-seq and ISL1 ChIP-seq analyses. Results: Analyses of these data revealed that ISL1 acts upstream of multiple oncogenic genes and pathways essential for neuroblastoma proliferation and differentiation, including LMO1 and LIN28B. ISL1 promotes expression of a number of cell cycle associated genes, but represses differentiation associated genes including RA receptors and the downstream target genes EPAS1 and CDKN1A. Consequently, Knockdown of ISL1 inhibits neuroblastoma cell proliferation and migration in vitro and impedes tumor growth in vivo, and enhances neuronal differentiation by RA treatment. Furthermore, genome-wide mapping revealed a substantial co-occupancy of binding regions by ISL1 and GATA3, and ISL1 physically interacts with GATA3, and together they synergistically regulate the aforementioned oncogenic pathways. In addition, analyses of the roles of ISL1 and MYCN in MYCN-amplified and MYCN non-amplified neuroblastoma cells revealed an epistatic relationship between ISL1 and MYCN. ISL1 and MYCN function in parallel to regulate common yet distinct oncogenic pathways in neuroblastoma. Conclusion: Our study has demonstrated that ISL1 plays an essential role in neuroblastoma regulatory networks and may serve as a potential therapeutic target in neuroblastoma.