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Background  Glucosamine 6-phosphate  N -acetyltransferase (GNPNAT1) is a key enzyme in the hexosamine biosynthetic pathway (HBP), which functions as promoting proliferation in some tumors, yet its potential biological function and mechanism in lung adenocarcinoma (LUAD) have not been explored.    Methods  The mRNA differential expression of GNPNAT1 in LUAD and normal tissues was analyzed using the Cancer Genome Atlas (TCGA) database and validated by real-time PCR. The clinical value of GNPNAT1 in LUAD was investigated based on the data from the TCGA database. Then, immunohistochemistry (IHC) of GNPNAT1 was applied to verify the expression and clinical significance in LUAD from the protein level. The relationship between GNPNAT1 and epigenetics was explored using the cBioPortal database, and the miRNAs regulating GNPNAT1 were found using the miRNA database. The association between GNPNAT1 expression and tumor-infiltrating immune cells in LUAD was observed through the Tumor IMmune Estimation Resource (TIMER). Finally, Gene set enrichment analysis (GSEA) was used to explore the biological signaling pathways involved in GNPNAT1 in LUAD.    Results  GNPNAT1 was upregulated in LUAD compared with normal tissues, which was verified through qRT-PCR in different cell lines ( P  < 0.05), and associated with patients’ clinical stage, tumor size, and lymphatic metastasis status (all  P  < 0.01). Kaplan–Meier (KM) analysis suggested that patients with upregulated GNPNAT1 had a relatively poor prognosis ( P  < 0.0001). Furthermore, multivariate Cox regression analysis indicated that GNPNAT1 was an independent prognostic factor for LUAD (OS, TCGA dataset: HR = 1.028, 95%  CI : 1.013–1.044,  P  < 0.001; OS, validation set: HR = 1.313, 95%  CI : 1.130–1.526,  P  < 0.001). GNPNAT1 overexpression was correlated with DNA copy amplification ( P  < 0.0001), low DNA methylation ( R  = −0.52,  P  < 0.0001), and downregulation of hsa-miR-30d-3p ( R  = −0.17,  P  < 0.001). GNPNAT1 expression was linked to B cells ( R  = −0.304,  P  < 0.0001), CD4 + T cells ( R  = −0.218,  P  < 0.0001), and dendritic cells ( R  = −0.137,  P  = 0.002). Eventually, GSEA showed that the signaling pathways of the cell cycle, ubiquitin-mediated proteolysis, mismatch repair and p53 were enriched in the GNPNAT1 overexpression group.    Conclusion  GNPNAT1 may be a potential prognostic biomarker and novel target for intervention in LUAD.

Upregulation of GNPNAT1 Predicts Poor Prognosis and Correlates With Immune Infiltration in Lung Adenocarcinoma