2. Academic Validation
  3. Low YTHDC1 Expression Upregulates FSCN1 to Promote Nuclear F-Actin Formation and Facilitate Double-strand DNA Breaks Repair in TMZ-Resistant Glioblastoma

Low YTHDC1 Expression Upregulates FSCN1 to Promote Nuclear F-Actin Formation and Facilitate Double-strand DNA Breaks Repair in TMZ-Resistant Glioblastoma

  • Adv Sci (Weinh). 2025 Dec 27:e13632. doi: 10.1002/advs.202513632.
Minglong Yang 1 2 3 4,  Wanxiang Niu 1 2 3 4,  Yuanfei Wang 1 2 3 4,  Peng Chen 1 2 3 4,  Maolin Mu 1 2 3 4,  Xiaoming Zhang 1 2 3 4,  Ben Xu 1 2 3 4,  Shanshan Hu 1 2 3 4,  Chaoshi Niu 1 2 3 4,  Pengfei Wu 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 2 Anhui Key Laboratory of Brain Function and Diseases, Hefei, Anhui, China.
  • 3 Anhui Provincial Stereotactic Neurosurgical Institute, Hefei, Anhui, China.
  • 4 Anhui Provincial Clinical Research Center for Neurosurgical Disease, Hefei, Anhui, China.
PMID: 41454694 DOI: 10.1002/advs.202513632
Abstract

Glioblastoma (GBM) is an aggressive and recurrent malignancy with a poor prognosis. Although temozolomide (TMZ) is a cornerstone of GBM treatment, its efficacy is often compromised by inherent or acquired resistance, underscoring the urgent need to uncover molecular mechanisms, discover new therapeutic targets, and develop innovative treatment strategies. In this study, we found an increased formation of filamentous actin (F-actin) within the nuclei of TMZ-resistant GBM cells. We also showed that overexpression of FSCN1 in TMZ-resistant GBM cells promotes F-actin formation and facilitates the repair of DNA double-strand breaks (DSBs). Further investigation revealed a marked decrease in the expression of YTHDC1 in TMZ-resistant GBM cells, which regulates FSCN1 through m6A modification. Additionally, FSCN1 activates the CDC42/N-WASP/Arp2/3 signaling pathway by recruiting FGD1 to activate CDC42GTP, which drives nuclear F-actin formation. Importantly, combining the FSCN1 inhibitor NP-G2-044, with TMZ therapy resulted in stronger anti-tumor effects both in vitro and in vivo. In conclusion, the study demonstrates that nuclear F-actin formation in GBM promotes DSB repair and reveals that targeting FSCN1 with NP-G2-044 could be a promising strategy for enhancing treatment outcomes and improving the prognosis for GBM patients.

Keywords

DSBs repair; clinical therapy; filamentous actin formation; glioblastoma; temozolomide resistance.

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