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FOXA1/UBE2T Inhibits CD8+T Cell Activity by Inducing Mediates Glycolysis in Lung Adenocarcinoma
Jiangtao Pu1, Dengguo Zhang1, Biao Wang1
1Department of Thoracic Surgery, Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China.
Background:
Immune escape is a key factor influencing survival rate of lung adenocarcinoma (LUAD) patients, but molecular mechanism of ubiquitin binding enzyme E2T (UBE2T) affecting immune escape of LUAD remains unclear. The objective was to probe role of UBE2T in LUAD.
Methods:
Bioinformatics means were adopted for analyzing UBE2T and forkhead box A1 (FOXA1) expression in LUAD tissues, the gene binding sites, the pathway UBE2T regulates, and the correlation between UBE2T and glycolysis genes. Dual luciferase and chromatin immunoprecipitation (ChIP) assays were conducted for validating the binding relationship between the two genes. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were employed to evaluate UBE2T, FOXA1, and programmed death ligand 1 (PD-L1) levels in cancer cells. MTT assay was conducted for detecting cell viability. Cytotoxicity assay detected CD8+T cell toxicity. Cytokine expression was assayed by enzyme linked immunosorbent assay (ELISA). Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were assayed by extracellular flow analyzer. Glycolytic gene expression was analyzed by qRT-PCR, and glycolysis-related indicators were detected by ELISA. Immunohistochemistry (IHC) detected CD8+T cell infiltration in tumor tissues.
Results:
FOXA1 and UBE2T were up-regulated in LUAD, and a binding site existed between UBE2T and FOXA1. Overexpressing UBE2T could increase PD-L1 expression and inhibit toxicity of CD8+T cells to LUAD cells. Overexpressing UBE2T repressed CD8+T cell activity in LUAD by activating the glycolysis pathway, and the addition of glycolysis inhibitor 2-deoxy-d-glucose (2-DG) reversed the above results. Mechanistically, FOXA1 promoted the immune escape of LUAD by up-regulating UBE2T and thus mediating glycolysis. In vivo experiments revealed that UBE2T knockdown hindered tumor growth, inhibited PD-L1 expression, and facilitated CD8+T cell infiltration.
Conclusion:
FOXA1 up-regulated the expression of UBE2T, which activated glycolysis, and thus inhibited activity of CD8+T cells, causing immune escape of LUAD.
Insights
Forkhead box A1 (FOXA1) promotes lung adenocarcinoma immune escape by upregulating ubiquitin binding enzyme E2T (UBE2T). UBE2T activates glycolysis, inhibiting CD8+ T cells and hindering anti-tumor immunity.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune escape significantly impacts lung adenocarcinoma (LUAD) patient survival.
- The precise molecular mechanisms by which ubiquitin binding enzyme E2T (UBE2T) influences LUAD immune escape remain largely unelucidated.
Purpose of the Study:
- To investigate the role of UBE2T in the immune escape of LUAD.
- To explore the regulatory relationship between UBE2T and forkhead box A1 (FOXA1) in LUAD progression.
Main Methods:
- Bioinformatic analysis of UBE2T and FOXA1 expression, gene binding sites, and pathway regulation in LUAD.
- Validation of gene interactions using dual luciferase and chromatin immunoprecipitation (ChIP) assays.
- Assessment of UBE2T, FOXA1, PD-L1, cell viability, CD8+ T cell cytotoxicity, cytokine expression, glycolysis, and T cell infiltration using qRT-PCR, western blot, MTT, cytotoxicity assays, ELISA, extracellular flow analysis, and IHC.
Main Results:
- UBE2T and FOXA1 were found to be upregulated in LUAD tissues, with a direct binding relationship identified.
- Increased UBE2T expression enhanced PD-L1 levels, suppressed CD8+ T cell toxicity, and promoted LUAD immune escape by activating the glycolysis pathway.
- Knockdown of UBE2T in vivo inhibited tumor growth, reduced PD-L1 expression, and increased CD8+ T cell infiltration.
Conclusions:
- FOXA1 acts as a key regulator, upregulating UBE2T expression in LUAD.
- UBE2T activation of the glycolysis pathway inhibits CD8+ T cell activity, leading to immune escape in LUAD.
- Targeting the FOXA1-UBE2T-glycolysis axis presents a potential therapeutic strategy for overcoming LUAD immune escape.
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