Abstract
PURPOSE: Glioblastoma (GBM) is the most common and aggressive primary brain tumor, characterized by poor prognosis and therapeutic resistance. Mesenchymal gliomas, in particular, exhibit more aggressive behavior and worse outcomes. This study investigates the role of CSRP2 in glioma progression and its epigenetic regulation of oncogenic pathways. METHODS: We analyzed TCGA, CGGA, and GEO datasets to identify genes enriched in mesenchymal gliomas and associated with poor prognosis. CSRP2 function was evaluated using CRISPR/Cas9 knockout in glioma cell lines and in xenograft models. Mechanism was examined by RNA-seq and promoter-focused CUT&Tag at the PDGFRA locus. RESULTS: CSRP2 is highly expressed in GBM, particularly in mesenchymal gliomas, and is associated with poor prognosis. Knockout of CSRP2 significantly inhibited glioma cell proliferation, migration, and invasion, and induced G2/M phase arrest. Transcriptomic analysis indicated that CSRP2 modulates tumor-associated gene programs, with PDGFRA emerging as a prominent target. CUT&Tag showed that CSRP2 co-occupies the PDGFRA promoter with the PRC1 components BMI1 and RNF2. CSRP2 knockout reduced BMI1 and RNF2 occupancy, decreased H3K27ac, and increased H2AK119ub1 at this promoter. These promoter-level changes were accompanied by lower PDGFRA transcription and attenuated PI3K/AKT signaling. CONCLUSIONS: Our data indicate that CSRP2 modulates glioma progression via PRC1-associated regulation at the PDGFRA promoter and downstream PDGFRA/PI3K/AKT signaling. CSRP2 may serve as a biomarker candidate. Therapeutic relevance remains to be established. CLINICAL TRIAL NUMBER: Not applicable. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13402-026-01167-9.