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Updated: Mar 25, 2026

The Clinical Application of Tumor Treating Fields Therapy in Glioblastoma
08:00

The Clinical Application of Tumor Treating Fields Therapy in Glioblastoma

Published on: April 16, 2019

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RFC4 drives temozolomide resistance in glioblastoma by activating STK38-BECN1-dependent autophagy

Min Mao1,2, Hang Ji3, Wen-Qian Yu4

  • 1The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, PR China.

Nature Communications
|March 24, 2026
PubMed

Insights

Replication factor RFC4 drives glioblastoma (GBM) resistance to temozolomide (TMZ) by stabilizing STK38, activating autophagy. Inhibiting this RFC4-STK38-BECN1 axis may overcome TMZ resistance in GBM patients.

Area of Science:

  • Neuro-oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Glioblastoma (GBM) is a fatal brain tumor with significant therapeutic resistance.
  • Autophagy plays a role in temozolomide (TMZ) resistance, but its regulatory mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the role of replication factor RFC4 in TMZ resistance in GBM.
  • To elucidate the molecular mechanism linking RFC4 to autophagy and TMZ resistance.

Main Methods:

  • Multi-omics analyses (genomics, transcriptomics, proteomics).
  • Molecular biology techniques including chromatin immunoprecipitation, Western blotting, and cell-based assays.
  • In vivo xenograft models in mice.

Main Results:

  • TMZ treatment increases chromatin accessibility, allowing YY1 transcription factor binding to the RFC4 promoter and upregulating RFC4 expression.
  • RFC4 stabilizes the kinase STK38, which is crucial for autophagosome formation.
  • The RFC4-STK38 interaction promotes BECN1 recruitment, activating autophagy and conferring TMZ resistance.
  • RFC4 overexpression leads to TMZ resistance in vivo, which is reversed by inhibiting autophagy.

Conclusions:

  • The RFC4-STK38-BECN1 signaling axis is a key mechanism driving TMZ resistance in GBM.
  • Targeting this axis presents a potential therapeutic strategy for overcoming treatment resistance in glioblastoma.

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