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Low YTHDC1 Expression Upregulates FSCN1 to Promote Nuclear F-Actin Formation and Facilitate Double-strand DNA Breaks

Minglong Yang1,2,3,4, Wanxiang Niu1,2,3,4, Yuanfei Wang1,2,3,4

  • 1Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 27, 2025
PubMed

Insights

Glioblastoma cells resistant to temozolomide show increased nuclear filamentous actin (F-actin). Targeting FSCN1 with NP-G2-044 enhances anti-tumor effects, offering a new strategy for glioblastoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis.
  • Temozolomide (TMZ) resistance limits GBM treatment efficacy, necessitating novel therapeutic targets.
  • Understanding resistance mechanisms is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the role of nuclear filamentous actin (F-actin) in TMZ-resistant GBM.
  • To identify molecular mechanisms driving F-actin formation and its impact on DNA repair.
  • To evaluate the therapeutic potential of targeting FSCN1 in GBM.

Main Methods:

  • Analysis of F-actin formation in TMZ-resistant GBM cells.
  • Investigating the role of FSCN1, YTHDC1, and the CDC42/N-WASP/Arp2/3 pathway.
  • Utilizing FSCN1 inhibitor NP-G2-044 in combination with TMZ.
  • In vitro and in vivo anti-tumor efficacy studies.

Main Results:

  • TMZ-resistant GBM cells exhibit increased nuclear F-actin.
  • FSCN1 overexpression promotes F-actin formation and DNA double-strand break (DSB) repair.
  • YTHDC1 downregulation correlates with TMZ resistance and regulates FSCN1 via m6A modification.
  • FSCN1 activates the CDC42/N-WASP/Arp2/3 pathway, driving nuclear F-actin.
  • Combined NP-G2-044 and TMZ therapy showed enhanced anti-tumor effects.

Conclusions:

  • Nuclear F-actin formation in GBM promotes DSB repair, contributing to TMZ resistance.
  • Targeting FSCN1 with NP-G2-044 is a promising strategy to overcome TMZ resistance.
  • This approach could improve treatment outcomes and prognosis for GBM patients.
Keywords:
DSBs repairclinical therapyfilamentous actin formationglioblastomatemozolomide resistance

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