PM2.5 promotes NSCLC carcinogenesis through translationally and transcriptionally activating DLAT-mediated glycolysis reprograming

Abstract

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.

Comprehensive analysis of cuproptosis-related prognostic gene signature and tumor immune microenvironment in HCC

“…Over expression of glycolytic gene DLAT, which promoted glycolysis but suppressed acetyl-CoA production and enhanced the malignancy of non-small cell lung cancer (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 ( Chen et al, 2022 ). GLS the first enzyme in glutaminolysis, is overexpressed in ibrutinib-resistant mantle cell lymphoma (MCL) cells, and that its expression correlates well with elevated glutamine dependency and glutaminolysis.…”

A Multi-Omics Analysis of NASH-Related Prognostic Biomarkers Associated with Drug Sensitivity and Immune Infiltration in Hepatocellular Carcinoma

“…We defined three common DEGs between NASH and HCC. DLAT, or dihydrolipoamide S-acetyltransferase, has been reported to mediate glycolysis reprogramming in non-small cell lung cancer [ 36 ]. It is also considered to be one of the key proteins regulating cuproptosis [ 37 ].…”

Role of cuproptosis-related gene in lung adenocarcinoma

“…DLAT (dihydrolipoamide S-acetyltransferase) is expressed in mitochondria which involved in cell glycolysis. A number of malignancies, including lung cancer ( 22 ), gastric cancer ( 23 ) and colon cancer ( 24 ), have been associated with high expression of DLAT in various tumors. These studies suggested a potential role of DLAT in abnormal cuproptosis metabolism in LUAD.…”