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Therapeutic targeting of circ-CUX1/EWSR1/MAZ axis inhibits glycolysis and neuroblastoma progression

Huanhuan Li1, Feng Yang1, Anpei Hu1

  • 1Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.

EMBO Molecular Medicine
|November 12, 2019
PubMed

Insights

CUT-like homeobox 1 (CUX1) and its circular RNA (circ-CUX1) drive aerobic glycolysis and neuroblastoma progression. Targeting the circ-CUX1/EWSR1/MAZ axis offers a new therapeutic strategy for this childhood cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Aerobic glycolysis is a key feature of tumor progression.
  • Mechanisms of glycolytic gene regulation in neuroblastoma (NB) are not fully understood.

Purpose of the Study:

  • To investigate the role of CUT-like homeobox 1 (CUX1) and circular RNA CUX1 (circ-CUX1) in regulating aerobic glycolysis and neuroblastoma progression.
  • To elucidate the molecular mechanisms underlying CUX1 and circ-CUX1 function in NB.

Main Methods:

  • Investigated the function of p110 CUX1 as a transcription factor.
  • Characterized the interaction of circ-CUX1 with EWSR1 and MAZ.
  • Utilized inhibitory peptides and lentiviral knockdown to block circ-CUX1 activity.
  • Analyzed CUX1 and circ-CUX1 expression in clinical NB samples.

Main Results:

  • p110 CUX1 enhances expression of key glycolytic enzymes (enolase 1, glucose-6-phosphate isomerase, phosphoglycerate kinase 1).
  • circ-CUX1 facilitates EWSR1-MAZ interaction, promoting MAZ transactivation and altered gene expression.
  • Inhibition of circ-CUX1-EWSR1 interaction or circ-CUX1 knockdown suppressed NB cell growth and aggressiveness.
  • CUX1 is an independent prognostic factor for unfavorable NB outcome; high circ-CUX1 correlates with lower survival.

Conclusions:

  • The circ-CUX1/EWSR1/MAZ axis is a critical regulator of aerobic glycolysis and neuroblastoma progression.
  • This axis represents a potential therapeutic target for neuroblastoma treatment.
Keywords:
CUT-like homeobox 1EWS RNA-binding protein 1MYC-associated zinc finger proteincircular RNAtumor progression

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