Therapeutic Targeting of Circ-CUX1/EWSR1/MAZ Axis Inhibits Glycolysis and Neuroblastoma Progression

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2019 Nov 12

PMID 31709724

Citations 87

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

Affiliations

Soon will be listed here.

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.

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