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.
Highlights
Neuroblastoma (NB), a malignant tumor arising from primitive neural crest, accounts for 15% of cancer-related mortality in childhood (Brodeur, 2003)
Elevated circ-CUT-like homeobox 1 (CUX1) promotes the aerobic glycolysis, growth, and aggressiveness of NB cells by binding to EWS RNA-binding protein 1 (EWSR1) and facilitating its interaction with MYC-associated zinc finger protein (MAZ), resulting in MAZ transactivation and transcriptional alteration of CUX1 and other genes associated with tumor progression, suggesting
We found 52 transcription factors consistently associated with these clinical features (Fig 1A), which were subjective to further overlapping analysis with potential transcription factors regulating all of 8 glycolytic genes revealed by Genomatix program
Summary
Neuroblastoma (NB), a malignant tumor arising from primitive neural crest, accounts for 15% of cancer-related mortality in childhood (Brodeur, 2003). For high-risk NB, the clinical outcome remains poor in despite of multimodal therapeutic approaches (Brodeur, 2003). To support their tumorigenecity and aggressiveness, tumor cells uptake and convert a large amount of glucose into lactic acid even in the presence of adequate oxygen, which is known as aerobic glycolysis or Warburg effect (Hanahan & Weinberg, 2011). Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs that are generated from exons or introns, and may function as microRNA (miRNA) sponges, regulators of transcription and splicing, or partners of RNA-binding protein (RBP) (Lasda & Parker, 2014; Li et al, 2015b). Intronic circRNAs, such as ci-ankrd, are able to regulate transcription efficiency of parental genes by binding to RNA polymerase II (Zhang et al, 2013). The roles of circRNAs in aerobic glycolysis during tumor progression remain largely elusive
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