Epigenetically regulated ZCCHC9 plays a pro-tumorigenic role in glioma based on a multi-omics analysis.

Glioma, a primary intracranial malignancy with high morbidity and mortality, remains therapeutically challenging despite of advances in targeted and immune therapies. ZCCHC9, a ZCCHC family member predominantly expressed in brain cortex, has documented roles in cervical and non-small cell lung cancer, yet its function, mechanism, and clinical significance in glioma is unclear. Through multi-omics analyses leveraging TCGA, CGGA, and HPA platforms, we identified aberrant up-regulation of ZCCHC9 in glioma, particularly in grade IV, older patients, and adverse molecular subtypes, e.g., IDH wild-type, and 1p/19q non-codeletion. ZCCHC9 potentially serves as an independent biomarker for poor prognosis and diagnosis, proven by Kaplan-Meier, Cox regression, and ROC curve analyses. Reduced DNA methylation on ZCCHC9's promoter is related to a worse survival. Additionally, ZCCHC9 can remodel tumor microenvironment by promoting immune infiltration and response, influence RNA modification, and exhibit broad interactions with miRNAs, lncRNAs/circRNAs/pseudogenes. Drug-sensitivity profiling revealed its binding affinity with Temozolomide, Dabrafenib, and Trametinib. Functional validation through in vitro and in vivo experiments confirmed ZCCHC9's oncogenic role in driving proliferation and migration, while suppressing apoptosis. Collectively, ZCCHC9 induces glioma progression by immune modulation, epigenetic dys-regulation, and therapeutic resistance, positioning it as a promising diagnostic biomarker, prognostic indicator, and therapeutic target.