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Background  Aerobic glycolysis is a hallmark of metabolic reprogramming that contributes to tumor progression. However, the mechanisms regulating expression of glycolytic genes in neuroblastoma (NB), the most common extracranial solid tumor in childhood, still remain elusive.    Methods  Crucial transcriptional regulators and their downstream glycolytic genes were identified by integrative analysis of a publicly available expression profiling dataset. In vitro and in vivo assays were undertaken to explore the biological effects and underlying mechanisms of transcriptional regulators in NB cells. Survival analysis was performed by using Kaplan-Meier method and log-rank test.    Results  Hepatocyte nuclear factor 4 alpha ( HNF4A ) and its derived long noncoding RNA ( HNF4A-AS1 ) promoted aerobic glycolysis and NB progression. Gain- and loss-of-function studies indicated that  HNF4A  and  HNF4A-AS1  facilitated the glycolysis process, glucose uptake, lactate production, and ATP levels of NB cells. Mechanistically, transcription factor HNF4A increased the expression of hexokinase 2 ( HK2 ) and solute carrier family 2 member 1 ( SLC2A1 ), while  HNF4A-AS1  bound to heterogeneous nuclear ribonucleoprotein U (hnRNPU) to facilitate its interaction with CCCTC-binding factor (CTCF), resulting in transactivation of CTCF and transcriptional alteration of  HNF4A  and other genes associated with tumor progression. Administration of a small peptide blocking  HNF4A-AS1 -hnRNPU interaction or lentivirus-mediated short hairpin RNA targeting  HNF4A-AS1  significantly suppressed aerobic glycolysis, tumorigenesis, and aggressiveness of NB cells. In clinical NB cases, high expression of  HNF4A-AS1 ,  hnRNPU ,  CTCF , or  HNF4A  was associated with poor survival of patients.    Conclusions  These findings suggest that therapeutic targeting of  HNF4A-AS1 /hnRNPU/CTCF axis inhibits aerobic glycolysis and NB progression.

RETRACTED ARTICLE: HNF4A-AS1/hnRNPU/CTCF axis as a therapeutic target for aerobic glycolysis and neuroblastoma progression