Open AccessTherapeutic targeting of circ‐ CUX 1 / EWSR 1/ MAZ axis inhibits glycolysis and neuroblastoma progression
Author(s) -
Li Huanhuan,
Yang Feng,
Hu Anpei,
Wang Xiaojing,
Fang Erhu,
Chen Yajun,
Li Dan,
Song Huajie,
Wang Jianqun,
Guo Yanhua,
Liu Yang,
Li Hongjun,
Huang Kai,
Zheng Liduan,
Tong Qiangsong
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201910835
Subject(s) - neuroblastoma , glycolysis , chemistry , cancer research , pharmacology , medicine , biochemistry , biology , metabolism , cell culture , genetics
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 ( CUX 1 ) and CUX 1 ‐generated circular RNA ( circ‐ CUX 1 ) contribute to aerobic glycolysis and NB progression. Mechanistically, p110 CUX 1, a transcription factor generated by proteolytic processing of p200 CUX 1, promotes the expression of enolase 1, glucose‐6‐phosphate isomerase, and phosphoglycerate kinase 1, while circ‐ CUX 1 binds to EWS RNA ‐binding protein 1 ( EWSR 1) to facilitate its interaction with MYC ‐associated zinc finger protein ( MAZ ), resulting in transactivation of MAZ and transcriptional alteration of CUX 1 and other genes associated with tumor progression. Administration of an inhibitory peptide blocking circ‐ CUX 1 ‐ EWSR 1 interaction or lentivirus mediating circ‐ CUX 1 knockdown suppresses aerobic glycolysis, growth, and aggressiveness of NB cells. In clinical NB cases, CUX 1 is an independent prognostic factor for unfavorable outcome, and patients with high circ‐ CUX 1 expression have lower survival probability. These results indicate circ‐ CUX 1 / EWSR 1/ MAZ axis as a therapeutic target for aerobic glycolysis and NB progression.