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.

中文翻译：

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circ-CUX1 / EWSR1 / MAZ轴的治疗靶向抑制糖酵解和神经母细胞瘤进展。

有氧糖酵解是肿瘤进展中代谢重编程的标志。但是，在儿童时期最常见的颅外恶性肿瘤神经母细胞瘤（NB）中，调节糖酵解基因表达的机制仍然难以捉摸。在这里，我们确定CUT样同源盒1（CUX1）和CUX1生成的环状RNA（circ-CUX1）有助于有氧糖酵解和NB的进展。从机理上讲，p110 CUX1是通过蛋白水解处理p200 CUX1产生的转录因子，可促进烯醇酶1，葡萄糖6磷酸异构酶和磷酸甘油酸激酶1的表达，而circ-CUX1与EWS RNA结合蛋白1（EWSR1）结合。促进其与MYC相关的锌指蛋白（MAZ）的相互作用，从而导致MAZ的反式激活以及CUX1和与肿瘤进展相关的其他基因的转录改变。抑制性肽的阻断circ-CUX1-EWSR1相互作用或慢病毒介导circ-CUX1敲低抑制了NB细胞的有氧糖酵解，生长和侵袭性。在临床NB病例中，CUX1是不良预后的独立预后因素，而circ-CUX1表达高的患者存活率较低。这些结果表明，circ-CUX1 / EWSR1 / MAZ轴可作为有氧糖酵解和NB进展的治疗靶标。