DZIP3 is associated with the cytoskeletal dynamics in glioblastoma and mitochondrial machinery regulation

Glioblastoma (GBM) is a major public health issue with increased prevalence and incidence worldwide. The therapeutic strategy is based on surgical resection, followed by chemotherapy and radiotherapy. However, therapeutic failure is increasingly recognized as driven by the intricate characteristics of the tumor microenvironment (TME). Stress granules (SGs) are structures that emerge in cells in response to stress. In GBM, these elements are implicated in tumor development and progression. Heterogeneous elements coalesce to form SGs, with RNA-binding proteins (RBPs) among them. DZIP3, DAZ-interacting zinc finger 3, is an understudied RBP in cancer, particularly with respect to its impact on TME remodeling. In the current study, we evaluate the prognostic value of DZIP3 using The Cancer Genome Atlas and the Chinese Glioma Genome Atlas as the validation cohort. Furthermore, we identified enriched pathways associated with upregulated genes linked to high DZIP3 expression. The correlation between these gene sets and DZIP3 was validated using a robustness assessment. We also identified the core hub miRNAs that target DZIP3 by using validated miRNA databases. Our results revealed that initially, high DZIP3 expression was associated with better survival in the TCGA cohort, but after adjustment for age, gender, transcription subtypes, IDH mutation status, MGMT promoter methylation status, and Karnofsky performance score, the prognostic utility of DZIP3 did not persist. Similar results were observed in the CGGA cohort. Of the 30 enriched pathways obtained, only 7 retained independent association: the cytoskeletal dynamics/intracellular transport gene set was the strongest correlate of DZIP3, followed by 4 mitochondrial modules (branched-chain amino acid metabolism, NAD biosynthesis, translation factors, and pyruvate metabolism), RNA granule/neurodegeneration gene set, and the nucleocytoplasmic transport gene set. The immune checkpoints, P-bodies, and malignant cell state gene sets were not independent of this signal. The cytoskeletal signal was replicated in the CGGA cohort and at single-cell resolution, with 9 core hub miRNAs targeting DZIP3, suspected to be a regulatory mechanism. Altogether, this study identifies the cytoskeletal module, 4 mitochondrial programs, RNA granule/neurodegeneration, and nucleocytoplasmic transport gene sets as the strongest correlates of DZIP3 expression in GBM, demonstrating that clinical prognostic value is distinct from transcriptional reproducibility.