Abstract
BackgroundAerobic 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.MethodsCrucial 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.ResultsHepatocyte 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.ConclusionsThese findings suggest that therapeutic targeting of HNF4A-AS1/hnRNPU/CTCF axis inhibits aerobic glycolysis and NB progression.
Highlights
Aerobic glycolysis is a hallmark of metabolic reprogramming that contributes to tumor progression
Hepatocyte nuclear factor 4 alpha (HNF4A)-AS1 promotes aerobic glycolysis, growth, and aggressiveness of NB cells by binding to heterogeneous nuclear ribonucleoprotein U and facilitating its interaction with CCCTC-binding factor (CTCF), resulting in transactivation of CTCF and transcriptional alteration of HNF4A and other genes associated with tumor progression, indicating the crucial roles of HNF4A-AS1/hnRNPU/CTCF axis in NB progression
We found 330 transcription factors consistently associated with these clinical features of NB cases, which were subjective to further over-lapping analysis with 36 transcription factors regulating 15 glycolytic genes analyzed by Chromatin immunoprecipitation (ChIP)-X program [24]
Summary
Aerobic glycolysis is a hallmark of metabolic reprogramming that contributes to tumor progression. The mechanisms regulating expression of glycolytic genes in neuroblastoma (NB), the most common extracranial solid tumor in childhood, still remain elusive. Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, and accounts for 15% of pediatric cancer deaths [1]. To maintain tumorigenesis and aggressiveness, tumor cells exert a unique metabolic. Activation of oncogenes or inactivation of tumor suppressors contributes to glycolytic gene expression in tumor cells. Inhibition of aerobic glycolysis by small organic molecules, such as 3-bromopyruvate or 2-deoxyglucose (2-DG), exhibits therapeutic potential for tumors [6, 7]. It is important to investigate the regulators of aerobic glycolysis for improving therapeutic efficiencies of NB
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