Cell division cycle 25 C (CDC25C) mediates cell-cycle progression and immune evasion in glioma

Gliomas are highly aggressive brain tumors with poor outcomes. CDC25C, a phosphatase that activates the CDK1-Cyclin B1 complex at the G₂/M checkpoint, is implicated in several cancers but its role in glioma progression and tumor immunity remains unclear.

We integrated bulk transcriptomic datasets (TCGA, CGGA, GEO) and single-cell RNA sequencing data to evaluate CDC25C expression, prognostic significance, and associated pathways in gliomas. Immune cell infiltration and checkpoint gene correlations were assessed via computational deconvolution. Additionally, U87MG glioma cells were transfected with siRNAs targeting CDC25C to achieve transient knockdown. Proliferation was measured by EdU incorporation, cell-cycle distribution by flow cytometry, and expression of G₂/M regulators (Cyclin B1, CDK1, phospho-CDK1) by Western blot.

CDC25C was overexpressed in gliomas compared to normal brain, and high CDC25C levels correlated with advanced tumor grade, other poor prognostic markers, and shorter overall survival. Gene set analyses revealed CDC25C-high tumors were enriched in cell-cycle and immunosuppressive pathways. High CDC25C expression was associated with greater infiltration of regulatory T cells (Tregs) and M0 macrophages, alongside upregulation of immune checkpoints PD-1, PD-L1, and CD80. Single-cell RNA-seq localized CDC25C-driven proliferation to a hyperproliferative MKI67-positive tumor cell subpopulation. Functionally, CDC25C knockdown in U87MG cells suppressed proliferation, induced G₂/M arrest, and inhibited the CDK1-Cyclin B1 mitotic axis.

CDC25C is a critical driver of glioma cell proliferation and an enabler of immune evasion. Its overexpression may link unchecked mitotic progression with an immunosuppressive microenvironment, underscoring CDC25C as a promising prognostic biomarker and therapeutic target in glioma.