Therapeutic targeting of circ-CUX1/EWSR1/MAZ axis inhibits glycolysis and neuroblastoma progression
Therapeutic targeting of circ-CUX1/EWSR1/MAZ axis inhibits glycolysis and neuroblastoma progression
复制标题
circ-CUX1/EWSR1/MAZ 轴的治疗靶向抑制糖酵解和神经母细胞瘤进展
DOI：
10.15252/emmm.201910835
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发表时间：
2019-11-11
影响因子：
11.1
通讯作者：
Tong, Qiangsong
中科院分区：
文献类型：
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作者：
Li, Huanhuan;Yang, Feng;Tong, Qiangsong
有氧糖酵解是肿瘤进展中代谢重编程的标志。然而，神经母细胞瘤（NB）是儿童期最常见的颅外恶性肿瘤，其糖酵解基因表达的调控机制仍不清楚。在此，我们确定CUT样同源框1（CUX 1）和CUX 1产生的环状RNA（circ-CUX 1）有助于有氧糖酵解和NB进展。机制上，p110 CUX 1，一种通过p200 CUX 1的蛋白水解加工产生的转录因子，促进烯醇化酶1、葡萄糖-6-磷酸异构酶和磷酸甘油酸激酶1的表达，而circ-CUX 1结合EWS RNA结合蛋白1（EWSR 1）以促进其与MYC相关锌指蛋白（MAZ）的相互作用，导致MAZ的反式激活和CUX 1和其他与肿瘤进展相关的基因的转录改变。施用阻断circ-CUX 1-EWSR 1相互作用的抑制肽或介导circ-CUX 1敲低的慢病毒抑制NB细胞的有氧糖酵解、生长和侵袭性。在临床NB病例中，CUX 1是不利结局的独立预后因素，circ-CUX 1高表达的患者生存概率较低。这些结果表明circ-CUX 1/EWSR 1/MAZ轴作为有氧糖酵解和NB进展的治疗靶点。
Aerobic glycolysis is a hallmark of metabolic reprogramming in tumor progression. However, the mechanisms regulating glycolytic gene expression remain elusive in neuroblastoma (NB), the most common extracranial malignancy in childhood. Herein, we identify that CUT-like homeobox 1 (CUX1) and CUX1-generated circular RNA (circ-CUX1) contribute to aerobic glycolysis and NB progression. Mechanistically, p110 CUX1, a transcription factor generated by proteolytic processing of p200 CUX1, promotes the expression of enolase 1, glucose-6-phosphate isomerase, and phosphoglycerate kinase 1, while circ-CUX1 binds to EWS RNA-binding protein 1 (EWSR1) to facilitate its interaction with MYC-associated zinc finger protein (MAZ), resulting in transactivation of MAZ and transcriptional alteration of CUX1 and other genes associated with tumor progression. Administration of an inhibitory peptide blocking circ-CUX1-EWSR1 interaction or lentivirus mediating circ-CUX1 knockdown suppresses aerobic glycolysis, growth, and aggressiveness of NB cells. In clinical NB cases, CUX1 is an independent prognostic factor for unfavorable outcome, and patients with high circ-CUX1 expression have lower survival probability. These results indicate circ-CUX1/EWSR1/MAZ axis as a therapeutic target for aerobic glycolysis and NB progression.