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RBFOX2 suppresses NETosis and glioma growth via 5hmC-dependent PDGFB decay

Xi Chen1, Weiwei Dai1, Hanlin Wang2

  • 1Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Microbiology, Key Laboratory of Medical Molecular Virology (Ministry of Education/ National Health Commission/ Chinese Academy of Medical Sciences), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Nanhu Laboratory, Jiaxing, Zhejiang Province 314002, China.

Cell Reports
|June 12, 2026
PubMed

Insights

The RNA-binding protein RBFOX2 acts as a tumor suppressor in glioma by inhibiting cell growth and NETosis. Reduced RBFOX2 levels correlate with poor patient survival, highlighting its therapeutic potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Neutrophil extracellular traps (NETs) play a role in tumor progression, but the mechanisms controlling their induction in cancer are not fully understood.
  • Identifying regulators of NETosis in the tumor microenvironment is crucial for developing novel cancer therapies.

Purpose of the Study:

  • To identify molecular mechanisms regulating NETosis in glioma.
  • To investigate the role of the RNA-binding protein RBFOX2 in glioma progression and NETosis.

Main Methods:

  • Analysis of RBFOX2 expression in glioma patient data.
  • Investigating the interaction of RBFOX2 with PDGFB mRNA and its effect on mRNA decay.
  • Assessing the impact of RBFOX2 on AKT-SP1 signaling and CSF3 transcription.
  • Evaluating NET formation in vivo using PAD4-/- mice and CSF3 neutralization.

Main Results:

  • RBFOX2 expression is significantly reduced in glioma and inversely correlates with patient survival.
  • RBFOX2 binds to 5-hydroxymethylcytidine-modified PDGFB mRNA, promoting its decay.
  • RBFOX2 represses CSF3 transcription, thereby limiting neutrophil-mediated NET formation.
  • RBFOX2 restrains glioma cell proliferation and NETosis, acting as a tumor suppressor.

Conclusions:

  • RBFOX2 functions as a tumor suppressor in glioma by controlling NETosis through a 5hmC-dependent post-transcriptional mechanism.
  • RBFOX2 represents a potential biomarker and therapeutic target for glioma.
  • This study establishes a link between RNA-binding proteins, RNA modification, and immune regulation in cancer evolution.
Keywords:
CP: cancerNETosisRBFOX2gliomatumor microenvironment

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