Therapeutic targeting of circ‐CUX1/EWSR1/MAZ axis inhibits glycolysis and neuroblastoma progression

• Main Authors: Huanhuan Li, Feng Yang, Anpei Hu, Xiaojing Wang, Erhu Fang, Yajun Chen, Dan Li, Huajie Song, Jianqun Wang, Yanhua Guo, Yang Liu, Hongjun Li, Kai Huang, Liduan Zheng, Qiangsong Tong
• Format: Article
• Language: English
• Published: Wiley 2019-12-01
• Series: EMBO Molecular Medicine
• Subjects: circular RNA; CUT‐like homeobox 1; EWS RNA‐binding protein 1; MYC‐associated zinc finger protein; tumor progression
• Online Access: https://doi.org/10.15252/emmm.201910835

Abstract 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.