DIAPH3 is upregulated in high-grade gliomas and linked to chromosomal instability.

ABSTRACT: BackgroundDiaphanous-related formin 3 (DIAPH3) is a member of the formin family, a group of proteins that regulate actin and microtubule dynamics. During mitosis, DIAPH3 localizes specifically to the centrosome. Its loss destabilizes microtubules and disrupts mitotic spindle polarity, leading to multipolar mitoses and abnormal chromosome segregation, which ultimately causes aneuploidy in daughter cells. METHODS: We investigated DIAPH3 expression in glioma samples-including low-grade and high-grade gliomas-using publicly available datasets (The Cancer Genome Atlas and a single-cell RNA-seq study). We also explored the impact of DIAPH3 expression on aneuploidy in cultured glioblastoma cells. RESULTS: DIAPH3 expression was specifically increased in grade 4 gliomas. However, its prognostic value did not surpass that of the WHO CNS5 glioma classification. DIAPH3 was predominantly expressed in mitotic cells and showed strong coexpression with genes involved in cell division, particularly those regulating mitotic progression and chromosome segregation. Several transcription factors known to drive proliferation and cancer progression may regulate DIAPH3 expression. In glioblastoma cell lines, we confirmed that DIAPH3 is upregulated during mitosis and that its knockdown increases aneuploidy. CONCLUSIONS: These findings confirm the role of DIAPH3 in chromosome segregation in clinical glioma samples and demonstrate its association with high-grade, poor-prognosis gliomas.