PM2.5 promotes NSCLC carcinogenesis through translationally and transcriptionally activating DLAT-mediated glycolysis
Qianqian Chen1,2, Yiling Wang1,2, Lin Yang3
1School of Public Health, Shenzhen University Health Science Center, 1066 Xueyuan Ave, Shenzhen, 518055, China.
Background:
Airborne fine particulate matter (PM2.5) has been associated with lung cancer development and progression in never smokers. However, the molecular mechanisms underlying PM2.5-induced lung cancer remain largely unknown. The aim of this study was to explore the mechanisms by which PM2.5 regulated the carcinogenesis of non-small cell lung cancer (NSCLC).
Methods:
Paralleled ribosome sequencing (Ribo-seq) and RNA sequencing (RNA-seq) were performed to identify PM2.5-associated genes for further study. Quantitative real time-PCR (qRT-PCR), Western blot, and immunohistochemistry (IHC) were used to determine mRNA and protein expression levels in tissues and cells. The biological roles of PM2.5 and PM2.5-dysregulated gene were assessed by gain- and loss-of-function experiments, biochemical analyses, and Seahorse XF glycolysis stress assays. Human tissue microarray analysis and 18F-FDG PET/CT scans in patients with NSCLC were used to verify the experimental findings. Polysome fractionation experiments, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assay were implemented to explore the molecular mechanisms.
Results:
We found that PM2.5 induced a translation shift towards glycolysis pathway genes and increased glycolysis metabolism, as evidenced by increased L-lactate and pyruvate concentrations or higher extracellular acidification rate (ECAR) in vitro and in vivo. Particularly, PM2.5 enhanced the expression of glycolytic gene DLAT, which promoted glycolysis but suppressed acetyl-CoA production and enhanced the malignancy of NSCLC cells. Clinically, high expression of DLAT was positively associated with tumor size, poorer prognosis, and SUVmax values of 18F-FDG-PET/CT scans in patients with NSCLC. Mechanistically, PM2.5 activated eIF4E, consequently up-regulating the expression level of DLAT in polysomes. PM2.5 also stimulated transcription factor Sp1, which further augmented transcription activity of DLAT promoter.
Conclusions:
This study demonstrated that PM2.5-activated overexpression of DLAT and enhancement in glycolysis metabolism contributed to the tumorigenesis of NSCLC, suggesting that DLAT-associated pathway may be a therapeutic target for NSCLC.
Insights
Air pollution (PM2.5) promotes non-small cell lung cancer (NSCLC) by increasing the DLAT gene and glycolysis. Targeting DLAT may offer a new therapeutic strategy for NSCLC.
Area of Science:
- Environmental Health
- Molecular Biology
- Oncology
Background:
- Airborne fine particulate matter (PM2.5) is linked to lung cancer in non-smokers.
- Molecular mechanisms of PM2.5-induced lung cancer are not well understood.
- This study investigates PM2.5's role in non-small cell lung cancer (NSCLC) carcinogenesis.
Purpose of the Study:
- To elucidate the molecular mechanisms by which PM2.5 regulates NSCLC development.
- To identify key genes and pathways affected by PM2.5 exposure in lung cancer.
Main Methods:
- Utilized parallel ribosome sequencing (Ribo-seq) and RNA sequencing (RNA-seq).
- Validated gene and protein expression using qRT-PCR, Western blot, and IHC.
- Assessed biological roles via gain/loss-of-function, biochemical assays, and Seahorse XF glycolysis stress tests.
- Corroborated findings using human tissue microarrays and 18F-FDG PET/CT scans.
Main Results:
- PM2.5 exposure shifted translation towards glycolysis genes, increasing glycolysis metabolism.
- PM2.5 enhanced DLAT gene expression, promoting glycolysis and NSCLC cell malignancy.
- High DLAT expression correlated with larger tumor size, poorer prognosis, and higher SUVmax in NSCLC patients.
- Mechanistically, PM2.5 activated eIF4E and Sp1, upregulating DLAT transcription and translation.
Conclusions:
- PM2.5-induced DLAT overexpression and enhanced glycolysis contribute to NSCLC tumorigenesis.
- The DLAT-associated pathway presents a potential therapeutic target for NSCLC.
- Findings provide insights into environmental factors influencing lung cancer progression.
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