Regulation of 1-methylhistidine and dimethylglycine in lung adenocarcinoma by circUBAP2L via hsalet-7c/GAD1 axis

doi:10.3877/cma.j.issn.1674-6902.2025.02.013

Abstract

Abstract:

Objective

To investigate the roles of circular ubiquitin-associated protein 2-like（circUBAP2L），hsa-let-7c，and its target gene glutamate decarboxylase 1 （GAD1） in lung adenocarcinoma.

Methods

Small-RNA sequencing was used to identify differential expression of hsa-let-7c. Bioinformatics analysis and real-time polymerase chain reaction （PCR） were used to assess differential expression of circUBAP2L （the upstream gene of hsa-let-7c） and GAD1 （the downstream target gene）. Dual-luciferase reporter assays were conducted to validate the regulatory relationships between circUBAP2L and hsa-let-7c，as well as hsa-let-7c and GAD1. A lentivirus was used to construct a GAD1 overexpression model in A549 lung cancer cells. Transcriptomic RNA sequencing （RNA-seq） and metabolomic liquid chromatography-mass spectrometry （LC-MS） were performed to analyze GAD1-associated differential genes and metabolites. Multiomics integration was applied to explore the impact of GAD1 on amino acid metabolism in lung adenocarcinoma cells.

Results

Real-time PCR confirmed upregulated expression of circUBAP2L in lung adenocarcinoma （P＜0.01）. Analysis of TCGA and GTEx databases revealed reduced expression of hsa-let-7c in lung adenocarcinoma tissues （P ＜0.0001），which was further validated by small-RNA sequencing （P ＜0.01）.Transcriptomic sequencing showed elevated GAD1 expression in lung adenocarcinoma compared to normal tissues （ P = 0. 032 ）. Dual-luciferase reporter assays identified a binding site （ CTACCTCCGACAACCTATACCT） between circUBAP2L and hsa-let-7c，while LC-MS metabolomics revealed that the GAD1 gene locus （AACAUGU） on the hsa-let-7c promoter binds to GAD1. Transcriptomic and metabolomic analyses demonstrated that GAD1 overexpression in lung adenocarcinoma cells increased levels of 1-methylhistidine （log2FC=2.37，P=0.00023），L-erythro-4-hydroxyglutamate （log2FC=2.02，P=0.00055），and dimethylglycine （log2FC = 2.45，P = 0.00129），affecting glycine，serine，and threonine metabolism pathways （P=0.00059） and cancer-related pathways （P=0.00541）.

Conclusion

circUBAP2L regulates 1-methylhistidine and dimethylglycine metabolism in lung adenocarcinoma cells through the hsa-let-7c/GAD1 axis.

Key words: Lung adenocarcinoma, Circular ubiquitin associated protein 2-like, Hsa-let-7c, Glutamatedecarboxylase1, tumor metabolism

Zhenyi Xia, Yi Liu, Yucheng Ding, Hongxia Yuan, Xiaoyan Li, Tian Chen. Regulation of 1-methylhistidine and dimethylglycine in lung adenocarcinoma by circUBAP2L via hsalet-7c/GAD1 axis[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2025, 18(02): 273-278.

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