Molecular mechanisms of aneuploidy and glioblastoma aggressiveness induced by DIAPH3 loss
(2026)
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- Authors
- Supervisors
- Tajeddine, Nicolas
- Abstract
- DIAPH3, member of the formin family of proteins, regulates actin and microtubule dynamics and localizes to the centrosome during mitosis, where it contributes to spindle organization and chromosomal segregation. In the mouse brain, loss of Diaph3 disrupts karyokinesis in neural progenitors, leading to aneuploidy and apoptosis, underscoring its essential role in mitotic fidelity. Given the high level of chromosomal instability in glioblastoma, we investigated whether DIAPH3 deregulation contributes to tumor aggressiveness and therapy response. Using publicly available transcriptomic datasets (TCGA and single-cell RNA-seq), we found that DIAPH3 expression is specifically increased in grade 4 gliomas and strongly co-expressed with genes regulating mitotic progression and chromosome segregation. DIAPH3 was predominantly expressed in dividing cells, suggesting a mitosis- related function. 9 To explore its mechanistic role, we silenced DIAPH3 in human GBM cell lines with distinct p53 status, U87 (wild-type p53) and U251 (mutant p53), using siRNA or pharmacological inhibition. Loss of DIAPH3 induced aneuploidy, DNA damage and activation of the DNA damage response in p53-mutated U251 cells, while promoting G2/M cell cycle arrest in both U251 and U87 cells and decreasing cell survival in U87 cells. In U87 cells, co-suppression of p53 and DIAPH3 reproduced the phenotype observed in U251 cells, confirming that DIAPH3 status influences the cellular outcome observed. Functionally, DIAPH3 loss enhanced radiosensitivity response in p53-mutated U251cells. Together, these findings identify DIAPH3 as a key regulator of chromosomal stability and DDR in GBM suggesting its potential as a therapeutic target to improve radiotherapy outcomes.
- Affiliations
Citations
Jabbour, C. (2026). Molecular mechanisms of aneuploidy and glioblastoma aggressiveness induced by DIAPH3 loss.