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Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN

Steffen Fuchs1,2,3,4,5,6, Clara Danßmann7, Filippos Klironomos7

  • 1Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany. steffen.fuchs@charite.de.

Nature Communications
|July 4, 2023
PubMed

Insights

MYCN amplification suppresses circular RNA (circRNA) production in neuroblastoma, a pediatric cancer, through DHX9 RNA helicase. This study reveals specific circRNAs, like circARID1A, driving cancer growth.

Area of Science:

  • Molecular Biology
  • Genetics
  • Oncology

Background:

  • Circular RNAs (circRNAs) are regulatory molecules with identified roles in cancer.
  • Mechanisms by which circRNAs modulate gene expression in cancer remain incompletely understood.
  • Neuroblastoma, a pediatric malignancy, presents an opportunity to study circRNA dysregulation.

Purpose of the Study:

  • To investigate circRNA expression patterns in neuroblastoma.
  • To elucidate the role of MYCN amplification in circRNA biogenesis.
  • To identify specific circRNAs contributing to neuroblastoma pathogenesis.

Main Methods:

  • Deep whole-transcriptome sequencing of 104 primary neuroblastomas.
  • Analysis of circRNA expression in relation to MYCN amplification status.
  • Investigation of molecular interactions involving identified circRNAs and RNA-binding proteins.

Main Results:

  • MYCN amplification globally suppresses circRNA biogenesis, dependent on DHX9 RNA helicase.
  • Similar MYCN-driven circRNA suppression observed in medulloblastoma, suggesting a general mechanism.
  • Identified 25 circRNAs specifically upregulated in neuroblastoma, including circARID1A.
  • circARID1A promotes neuroblastoma cell growth and survival via interaction with KHSRP.

Conclusions:

  • MYCN plays a critical role in regulating circRNA expression in cancer.
  • DHX9 is a key mediator of MYCN's effect on circRNA biogenesis.
  • circARID1A is an oncogenic circRNA in neuroblastoma, highlighting specific circRNAs as therapeutic targets.

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