PARP4 drives tumor progression by promoting glioma cell proliferation and invasion as a potential therapeutic target

BACKGROUND: The malignant behavior of glioma is tightly associated with underlying complex molecular mechanisms. Poly(ADP-ribose) polymerase 4 (PARP4) has been implicated in several tumor types. Nevertheless, comprehensive studies addressing the role of PARP4 in glioma remain lacking. METHODS: Utilizing publicly available datasets including the Chinese Glioma Genome Atlas (CGGA), Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), Connectivity Map (cMap) and other bioinformatics tools, we systematically assessed PARP4 expression, its clinical relevance, prognostic significance, associated biological processes, immune infiltration, and potential inhibitors in glioma. In addition, we performed functional assays to validate its oncogenic role in glioblastoma (GBM) cells. RESULTS: Our findings revealed that PARP4 expression was elevated in gliomas compared to normal brain tissue, and that higher PARP4 levels correlated with increased tumor grade and worse patient prognosis. The immune-analysis suggested that immunotherapies targeting immune checkpoint genes may be beneficial for glioma patients with elevated PARP4 expression. Endogenous PARP4 knockdown impaired GBM cell proliferation, S/G₂ cell-cycle progression and migratory/invasive behavior. Finally, through molecular docking we identified five small-molecule compounds as potential PARP4 inhibitors. CONCLUSIONS: Taken together, our study demonstrated PARP4 acts as an important tumor-promoting factor by favoring glioblastoma (GBM) cell proliferation and migration/invasion. Our findings suggested that PARP4 might serve as a novel independent prognostic biomarker and a promising therapeutic target for glioma patients.