Targeting inhibition of prognosis-related nicotinamide metabolism genes, including poly (ADP-ribose) polymerase 9 (PARP-9) attenuates glioma progression

Abstract

Background Nicotinamide (NAM) metabolism plays a significant role in glioma development. This study aimed to investigate the correlation between NAM metabolic genes and prognosis, immune microenvironment, and tumor progression in glioma. Methods We analyzed the expression and prognostic significance of NAM-metabolism-related genes in patients with glioma to develop a new NAM metabolism-related signature (NMRS) and nomograms using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and compared the differences in gene set enrichment analysis (GSEA), protein-protein interaction networks, competing endogenous RNA (ceRNA) regulatory network, prognosis, mutation load, and immune landscape between different groups. Additionally, we employed Western blotting, cell proliferation and apoptosis analysis, Semi-quantitative Reverse Transcription-Polymerase Chain Reaction(SqRT-PCR), and a xenograft model in nude mice to investigate the role of PARP9 in tumor progression. Results Our study identified eight genes, including NT5C1A, NNMT, CDKN1A, PTGS2, PNP, PARP10, PARP14, and PARP9, that exhibited a significant correlation with glioma prognosis and could act as an independent indicator. Risk stratification was conducted based on the NMRS, and the low-risk group exhibited more favorable clinical results. The GSEA revealed that the low-risk group exhibited a significant enrichment in immune-associated pathways, while the high-risk group showed significant enrichment in cancer-related pathways. The ESTIMATE and single-sample GSEA algorithms indicated that the low-risk group displayed higher antitumor immunocyte infiltration. TIDE analysis revealed that the low-risk group responded more favorably to immunotherapy. Furthermore, validation experiments revealed that PARP9 is a proto-oncogene associated with the PARP9-JAK2-STAT3 signaling pathway. Conclusion We developed a new NMRS for predicting prognosis and treatment efficacy in glioma. The identified gene, PARP9, is a potential therapeutic target for glioma.