Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth.,Science Translational Medicine

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Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth.
Science Translational Medicine ( IF 15.8 ) Pub Date : 2020-02-19 , DOI: 10.1126/scitranslmed.aax8694
Yu-Feng Guo _{1,

2,

3} , Jiang-Jie Duan _{1,

2,

3} , Jun Wang _{1,

2,

3} , Lin Li _{1,

2,

3} , Di Wang _{1,

2,

3} , Xun-Zhou Liu _{1,

2} , Jing Yang _{2,

3} , Hua-Rong Zhang _{2,

3} , Jing Lv _{1,

2,

3} , Yong-Jun Yang _{1,

2,

3} , Ze-Yu Yang _{1,

2,

3} , Jiao Cai _{1,

2,

3} , Xue-Mei Liao _{1,

2,

3} , Tao Tang _{1,

2,

3} , Ting-Ting Huang _{1,

2,

3} , Feng Wu _{2,

3} , Xian-Yan Yang _{1,

2,

3} , Qian Wen _{1,

2,

3} , Xiu-Wu Bian _{2,

3} , Shi-Cang Yu _{1,

2,

3}

Affiliation

MYCN-amplified neuroblastoma (NB) is characterized by poor prognosis, and directly targeting MYCN has proven challenging. Here, we showed that aldehyde dehydrogenase family 18 member A1 (ALDH18A1) exerts profound impacts on the proliferation, self-renewal, and tumorigenicity of NB cells and is a potential risk factor in patients with NB, especially those with MYCN amplification. Mechanistic studies revealed that ALDH18A1 could both transcriptionally and posttranscriptionally regulate MYCN expression, with MYCN reciprocally transactivating ALDH18A1 and thus forming a positive feedback loop. Using molecular docking and screening, we identified an ALDH18A1-specific inhibitor, YG1702, and demonstrated that pharmacological inhibition of ALDH18A1 was sufficient to induce a less proliferative phenotype and confer tumor regression and prolonged survival in NB xenograft models, providing therapeutic insights into the disruption of this reciprocal regulatory loop in MYCN-amplified NB.

中文翻译：

抑制 ALDH18A1-MYCN 正反馈回路会减弱 MYCN 扩增的神经母细胞瘤的生长。

MYCN 扩增的神经母细胞瘤 (NB) 的特点是预后不良，直接靶向 MYCN 已被证明具有挑战性。在这里，我们发现醛脱氢酶家族 18 成员 A1 (ALDH18A1) 对 NB 细胞的增殖、自我更新和致瘤性产生深远影响，并且是 NB 患者，尤其是 MYCN 扩增患者的潜在危险因素。机制研究表明，ALDH18A1 可以在转录和转录后调节 MYCN 表达，MYCN 相互反式激活 ALDH18A1，从而形成正反馈回路。通过分子对接和筛选，我们鉴定了一种 ALDH18A1 特异性抑制剂 YG1702，

更新日期：2020-02-19

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