Background: Lung cancer is a common malignant tumor with high morbidity and mortality rate. Glucosamine 6-phosphate N-acetyltransferase (
GNPNAT1), which serves as a critical enzyme in hexosamine biosynthetic pathway (HBP), has been identified as a metastasis-associated gene and is upregulated in lung adenocarcinoma (LUAD). However, the exact role and related mechanism of
GNPNAT1 in LUAD metastasis remain unknown. Methods: We analyzed the expression of
GNPNAT1 in the public databases and confirmed the results by immunohistochemistry (IHC). The biological functions of
GNPNAT1 in LUAD were investigated based on The Cancer Genome Atlas (TCGA). Correlations between
GNPNAT1 and cancer immune characteristics were analyzed via the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) and Cell-type Identification by Estimating Relative Subsets of RNA Transcript (CIBERSORT) R package. The underlying mechanisms of altered
GNPNAT1 expression on LUAD cell tumorigenesis, proliferation, migration, invasion, and metastasis were explored in vitro and in vivo. Results: We demonstrated that
GNPNAT1 expression was significantly increased in LUAD and negatively associated with the overall survival (OS) of patients.
hsa-miR-1-3p and
hsa-miR-26a-5p were identified as upstream miRNA targets of
GNPNAT1.
GNPNAT1 was associated with the infiltration levels of CD8 T cells, memory-activated CD4 T cells, NK cells resting, macrophages M0, macrophages M1, neutrophils, gamma delta T cells, and eosinophils, while it was negatively correlated with memory-resting CD4 T cells, regulatory T cells (Tregs), resting NK cells, monocytes, resting dendritic cells, and resting mast cells.
GNPNAT1 knockdown significantly inhibited proliferation, migration, invasion, epithelial–mesenchymal transition (EMT) process, and metastasis of LUAD cells, while overexpression of
GNPNAT1 revealed the opposite effects. Rescue assay showed that
Snai2 knockdown reversed
GNPNAT1-induced LUAD cells migration, invasion, and EMT. Mechanistically,
GNPNAT1 promoted cancer cell metastasis via repressing ubiquitination degradation of
Snai2 in LUAD. Conclusions: Taken together, these data indicate that
GNPNAT1 serves as a prognostic biomarker for LUAD patient. Additionally,
GNPNAT1 is critical for promoting tumorigenesis and metastasis of LUAD cells and may be a potential therapeutic target for preventing LUAD metastasis.
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