Core transcriptional regulatory circuit-regulated IGF2BP3 stabilizes E2F2 mRNA via m6A modification in neuroblastoma

Carcinogenesis. 2025 Sep 4;46(3):bgaf040. doi: 10.1093/carcin/bgaf040.

Abstract

Neuroblastoma (NB) is a pediatric tumor with diverse outcomes and unknown underlying mechanisms. The core transcriptional regulatory circuit (CRC) and N6-methyladenosine (m6A) are key factors that control cell identity and fate. IGF2BP3 is an m6A reader protein that is transcriptionally regulated by CRC transcription factors (TFs). In NB, this molecule is abundantly expressed, and there is a clear correlation between its expression and a bad prognosis. We mechanistically demonstrated that IGF2BP3 promotes E2F2 mRNA expression through m6A, which is correlated with high risk and poor prognosis in NB patients. We showed that the CRC TF-IGF2BP3-E2F2 regulatory axis forms an oncogenic network that drives NB development and progression. Overall, we investigated the molecular mechanism by which IGF2BP3, a m6A-reading protein that is regulated by CRC TFs, regulates E2F2 mRNA expression in an m6A-dependent manner. This study highlights the therapeutic potential of disrupting this axis with m6A-targeted interventions.

Keywords: N6-methyladenosine (m6A); core transcriptional regulatory circuit (CRC); m6A reader; mRNA stability; neuroblastoma.

Plain language summary

IGF2BP3 binds to E2F2 mRNA through m6A modification thereby promoting NB progression, and the CRC TFs-IGF2BP3-E2F2 axis is involved in the regulation of NB progression.

MeSH terms

  • Adenosine* / analogs & derivatives
  • Adenosine* / genetics
  • Adenosine* / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • E2F2 Transcription Factor* / genetics
  • E2F2 Transcription Factor* / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Gene Regulatory Networks*
  • Humans
  • Mice
  • Neuroblastoma* / genetics
  • Neuroblastoma* / metabolism
  • Neuroblastoma* / mortality
  • Neuroblastoma* / pathology
  • Prognosis
  • RNA Stability
  • RNA, Messenger* / genetics
  • RNA, Messenger* / metabolism
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism

Substances

  • RNA-Binding Proteins
  • IGF2BP3 protein, human
  • Adenosine
  • N-methyladenosine
  • RNA, Messenger
  • E2F2 Transcription Factor
  • E2F2 protein, human