| Literature DB >> 32075946 |
Yu-Feng Guo1,2,3, Jiang-Jie Duan1,2,3, Jun Wang1,2,3, Lin Li1,2,3, Di Wang1,2,3, Xun-Zhou Liu1,2, Jing Yang2,3, Hua-Rong Zhang2,3, Jing Lv1,2,3, Yong-Jun Yang1,2,3, Ze-Yu Yang1,2,3, Jiao Cai1,2,3, Xue-Mei Liao1,2,3, Tao Tang1,2,3, Ting-Ting Huang1,2,3, Feng Wu2,3, Xian-Yan Yang1,2,3, Qian Wen1,2,3, Xiu-Wu Bian4,3, Shi-Cang Yu5,2,3.
Abstract
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.Entities:
Mesh：
Substances：
Year: 2020 PMID： 32075946 DOI： 10.1126/scitranslmed.aax8694
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 17.956