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

## TL;DR

Low YTHDC1 in glioblastoma cells increases FSCN1, which helps repair DNA damage and may be targeted with a new drug to improve treatment.

## Contribution

Identifies FSCN1 as a novel therapeutic target in TMZ-resistant glioblastoma through its role in nuclear F-actin formation and DNA repair.

## Key findings

- Low YTHDC1 expression upregulates FSCN1 via m6A modification in TMZ-resistant GBM cells.
- FSCN1 promotes nuclear F-actin formation through the CDC42/N-WASP/Arp2/3 pathway.
- Combining TMZ with FSCN1 inhibitor NP-G2-044 enhances anti-tumor effects in GBM.

## 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.

This study revealed that low expression of YTHDC1 in TMZ‐resistant GBM cells leads to increased FSCN1 expression, which is suppressed by m6A modification. FSCN1 activates the CDC42/N‐WASP/Arp2/3 axis in the cell nucleus by recruiting the guanine nucleotide exchange factor (GEF) family member FGD1, thereby promoting F‐actin polymerization in the nucleus. The study also identified the potential novel therapeutic strategy of combining TMZ with NP‐G2‐044. These findings provide theoretical support for combined therapies in the clinical treatment of GBM resistance.