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. 2025 Dec 21;4(4):754–767. doi: 10.1021/envhealth.5c00524

Coke Oven Emission Exposure Triggers Malignant Transformation of Lung Epithelial Cells by SFTA1P-Dependent Alteration of Acetyl-CoA Metabolism

Qiang Ju †,‡, Xinmei Li ‡,§, Zhaoxu Wu ‡, Pimei Zhang ‡, Hongguang Chen ‡, Jing Ji ‡, Wei Gao ‡,*, Yuxin Zheng ‡, Dianke Yu ‡, Yanjie Zhao ‡,*
PMCID: PMC13097155  PMID: 42022200

Abstract

Exposure to coke oven emissions (COEs) is an important environmental factor in lung cancer. A previous study revealed that 20 μg/mL COE exposure for 120 days could induce malignant transformation of lung epithelial cells. However, the underlying mechanism remains unclear. The epigenetic regulation of long noncoding RNAs (lncRNAs) plays an important role in carcinogenesis. Changes in lncRNA expression during COE-induced malignant transformation were detected, highlighting the importance of gene–environment interactions in cancer. Here, we identified that SFTA1P was downregulated in COE-induced malignant transformation of lung epithelial cells. Interestingly, this reduction was found to have a gradient effect on different stages of cells of COE exposure. Moreover, we found that downregulation of SFTA1P expression in lung cancer was related to patients’ poor prognosis. Phenotypic studies have demonstrated that SFTA1P suppressed lung cancer cell proliferation in vitro and in vivo. Further mechanistic studies revealed that SFTA1P directly interacts with ACSS2, an important enzyme responsible for synthesizing acetyl-CoA, leading to abnormal acetyl-CoA metabolism and affecting COE-induced lung carcinogenesis. COE-induced malignant transformed cells or cells with the knockdown of SFTA1P showed significantly increased fatty acid and cholesterol levels, while normal lung epithelial cells or cells with overexpression of SFTA1P showed substantially decreased fatty acid and cholesterol levels. Moreover, transfection of ACSS2 into cells with overexpressing SFTA1P could rescue the SFTA1P-induced cell phenotype. Our findings link SFTA1P-regulated acetyl-CoA metabolism with COE-induced malignant transformation and imply that SFTA1P could be an important biomarker for early intervention and diagnosis of lung cancer.

Keywords: coke oven emissions, lung cancer, SFTA1P, acetyl-CoA, metabolism

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Introduction

Coke oven emissions (COEs) are a kind of benzene-soluble substances produced under high temperature and hypoxic conditions in coking plants. − COEs contain various volatile organic compounds and particles, especially polycyclic aromatic hydrocarbons, which can damage the respiratory tract, digestive tract, and skin, causing respiratory diseases and skin inflammation. − The mechanisms underlying these effects include reactive oxygen species accumulation, oxidative DNA damage, and lipid peroxidation, among other pathological processes. , In 1984, the International Agency for Research on Cancer (IARC) listed COE as a clear carcinogen for humans. Epidemiological studies have shown that workers in coking plants are prone to lung carcinogenesis due to long-term exposure to COE. , Toxicological studies revealed that COE exposure could trigger malignant transformation of lung epithelial cells. , These findings demonstrated that COE is a possible threat to human health and deserves more attention. Understanding the mechanism of COE exposure-induced lung cancer may be beneficial for early detection and intervention of tumors.

Lung cancer occurs as a result of the interaction between the environment and genetics. However, it is insufficient to define the occurrence of cancer only in terms of genetics. Epigenetics is the link that connects the environment with genetics and cancer. Epigenetic changes are early molecular events in the development of cancer. In addition, epigenetic changes are also one of the main hallmarks of environmental damage. To date, studies on the relationship between COE exposure and epigenetic changes are still insufficient. The mechanism of COE–epigenetic interactions in COE-induced lung cancer requires further elucidation.

Long noncoding RNAs (lncRNAs), a class of RNAs with a length of more than 200 nucleotides and no ability to encode proteins, play vital roles in epigenetic regulation. − In the past, lncRNAs were regarded as “garbage products” with no function. , Emerging studies have confirmed that lncRNAs play important regulatory roles in environmental toxicant exposure. − In tumorigenesis and progression, the regulatory mechanisms of lncRNAs primarily involve the regulation of various metabolic enzymes, which integrate the processes of malignant cell transformation and metabolic reprogramming. lncRNA FAS-AS1 and HOTAIRM1 were abnormally expressed in the blood of leukemia workers exposed to benzene. , LncRNA-ENST000000446135 expression was significantly increased in the blood of workers exposed to cadmium. Moreover, lncRNA-ATB is upregulated upon exposure to coal factory dust, which can be used as a diagnostic marker for coal workers with pneumoconiosis. Upregulation of LncRNA PU.1 AS regulates arsenic-induced lipid metabolism. The above evidence strongly supports that the abnormal expression of lncRNAs is a common phenomenon under environmental toxicant exposure and encouraged us to investigate the expression and regulatory mechanism of lncRNAs in COE-induced cell malignant transformation. In our previous study, we found that 702 lncRNAs were abnormally expressed in the COE-induced malignant transformation cells. However, the screening of functional lncRNAs and their interaction mechanisms with metabolites is unclear.

In this study, we exposed human bronchial epithelial cells (16HBE) to COE organic extract to evaluate the molecular markers of malignant transformation. By integrating a chronic malignant transformation model, animal tumor formation assays, multiomics, and network approaches, this work provides insights into the underlying mechanisms of COE-induced carcinogenesis.

Materials and Methods

Cell Lines and Cell Culture

Normal human bronchial epithelial 16HBE cells and 16HBE-T cell lines were transformed by COE exposure. Specifically, the 16HBE-T cell line was obtained by inducing 16HBE cells with 20 μg/mL COE organic extract for 120 days and verified with the characteristics of lung squamous cell carcinoma (LUSC). The 75COE cell line was obtained by exposing 16HBE cells to 20 μg/mL of the COE organic extract for 75 days. NCI-H226 and NCI-H1703 are commonly used human LUSC cell lines in studies and were purchased from the National Collection of Authenticated Cell Cultures. Cell lines were identified by Short Tandem Repeat (STR) analysis and were free from mycoplasma infection. 16HBE and 16HBE-T cells were cultured in Minimum Essential Medium (Gibco) with 10% fetal bovine serum (Gibco). NCI-H226 and NCI-H1703 cells were cultured in RPMI 1640 medium with 10% fetal bovine serum (Gibco). All cells were grown in a 37 °C incubator with 5% CO2.

RNA Sequencing

Total RNA was extracted from 16HBE, 75COE, and 16HBE-T cells, and three replicates per group were sequenced by BioMiao Biological Technology (Beijing, China) on Illumina HiSeq1500 systems, according to the manufacturer’s protocol. Raw paired-end sequencing data was mapped to the Hg19 reference genome (UCSC) to produce normalized expression data for all transcripts, using the HISTA2 and featureCounts functions of the Subread package serially. EdgeR was implemented to identify differentially expressed lncRNAs. A P value <0.05 and Log2|FoldChange (FC) | > 1 were selected as the criteria for significant differentially expressed lncRNAs.

Analysis of Public Datasets

SFTA1P expression in LUSC and normal tissues was analyzed using TCGA data from the TANRIC database (https://ibl.mdanderson.org/tanric/_design/basic/query.html). Moreover, 445 LUSC patients were obtained from the TCGA database (https://www.cancer.gov/ccg/research/genome-sequencing/tcga) and used for the detection of SFTA1P levels in different stages. Survival analysis was performed using the Kaplan–Meier plotter database (https://kmplot.com/analysis/). The cBioPortal database (http://www.cbioportal.org) was used to analyze the genomic alterations of SFTA1P in pan-cancer.

RNA Extraction and Quantitative Real-Time PCR (qRT-PCR) Analysis

Total RNA was extracted from cells using TRIzol reagent (Invitrogen) and reverse-transcribed to complementary DNA (cDNA) using a PrimeScript RT reagent kit (Takara, Japan). qRT-PCR was performed in triplicate using TB Green Premix Ex TaqII (TaKaRa, Japan). Primers were synthesized by Tsingke Biotechnology (Tsingke, China), and the sequences are shown in Table S1.

Transient Transfection

Plasmids that overexpressed SFTA1P, AL031600.1, and AL124312.2 were synthesized by Generay Biotechnology (Shanghai, China) and transiently transfected into NCI-H1703 cells with Lipofectamine 3000 (Invitrogen). After 48 h of transfection, phenotypic assays were performed.

CCK8 Assay

Cells (3 × 103) that were transfected with plasmids or infected with lentivirus were inoculated into a 96-well plate. Cell viability was measured using the Cell Counting Kit-8 (Dojindo, Kumamoto, Japan) at 24, 48, 72, 96, and 120 h according to the manufacturer’s protocol.

Measurement of the Absolute Copy Number of SFTA1P Per Cell

The copy number of SFTA1P per cell was estimated using an absolute qRT–PCR method. We first plotted a standard curve using the limiting dilution method using in vitro-transcribed full-length SFTA1P DNA as the standard template. The SFTA1P copy number per cell was calculated according to the molecular weight and cell count.

Cytoplasmic and Nuclear Fractionation

Cytoplasmic and nuclear RNA were isolated and purified from 16HBE and NCI-H226 cells using the PARIS Kit (Life Technologies). Briefly, the cells were lysed with cell fractionation buffer and centrifuged at 4 °C. The supernatant was the cytoplasmic lysate. The pellet fraction was lysed with cell disruption buffer and incubated on ice to obtain a nuclear lysate. Then, RNAs were extracted from the cytoplasmic and nuclear lysates. qRT-PCR was performed to determine SFTA1P expression in the cytoplasm and nucleus.

RNA FISH Assay

RNA FISH assay was performed using a Fluorescent in Situ Hybridization Kit (RiboBio, Guangzhou, China) according to the manufacturer’s protocol. In brief, 16HBE and NCI-H226 cells were inoculated on poly-l-lysine-coated cell slides and fixed with 4% paraformaldehyde, followed by permeabilization with 0.5% Triton X-100 and blocking with prehybridization buffer. Then, cells were incubated with SFTA1P FISH Probe Mix. U6 and 18S RNA FISH Probe Mix were used as positive controls located in the nucleus and cytoplasm. Cells were washed with washing buffer containing 0.1% Tween-20 and stained with DAPI for 10 min. The slides were finalized and observed under a laser scanning confocal microscope (Olympus, Tokyo, Japan).

Construction of Stably Expressed Cell Lines

shRNA sequences targeting SFTA1P (#1:5′-GCACGAGUAAGCCAAACAATTUUGUUUGGCUUACUCGUGCTT-3′, #2:5′- GCAAAUAAGGGAGAGACAATTUUGUCUCUCCCUUAUUUGCTT-3′) or full-length SFTA1P cDNA were synthesized and subcloned into lentiviral expression vectors (GV493, GV502), respectively. Lentiviruses were packaged by Genechem (Shanghai, China). NCI-H226 and NCI-H1703 cells were infected with lentivirus and selected using 0.5 μg/mL puromycin.

Colony Formation Assay

Cells (1 × 103) that stably overexpressed or knocked down SFTA1P were inoculated in 6-well plates. After 2 weeks, the cells were fixed with methanol and stained with 0.1% crystal violet.

Animal Studies

Four-week-old female M-NSG mice (purchased from Shanghai Model Organism, China) were allowed to adapt to local animal breeding conditions for 1 week and were provided with sufficient food and water under a 12-h dark/12-h light cycle. Mice (five in each group) were injected subcutaneously with 100 μL of a cell suspension containing 5 × 106 cells in the left axillary. Tumor volume was measured every 5 days and calculated using the following formula: volume = length × width × width × 0.5. After 30 days, the mice were sacrificed. Then, the tumors were separated and photographed before being fixed for subsequent studies. All animal assays were approved by the Ethics Committee of the Medical College of Qingdao University (No: QDU-AEC-2023379) and carried out in compliance with the Animal Research Reporting of In vivo Experiments (ARRIVE) guidelines.

RNA Pull-Down and Mass Spectrometric Analysis

RNA pull-down assay was performed using the Pierce Magnetic RNA-Protein Pull-Down Kit (Thermo Scientific, 20164). Briefly, the SFTA1P overexpressed plasmid was used as a template, and the DNA double strand of SFTA1P was obtained by PCR amplification using the high-fidelity enzyme Q5. SFTA1P sense was transcribed in vitro using a TranscriptAid T7 High Yield Transcription Kit (Thermo Scientific, K0441) and biotinylated using a Pierce RNA 3′-End Desthiobiotinylation Kit (Thermo Scientific, 20163). The labeled RNA was then bound to streptavidin magnetic beads and incubated with a protein lysate extracted from NCI-H226 cells. RNA-binding proteins (RBPs) were washed and eluted for mass spectrometry and western blotting. The detailed procedures are provided in Text S1.

RNA Immunoprecipitation (RIP) Assay

RIP assay was performed using a Magna RIP RNA-Binding Protein Immunoprecipitation Kit (Millipore, 17-700). First, NCI-H226 cells were lysed in RIP lysis buffer and stored at −80 °C. Antibodies against ACSS2 were immunoprecipitated with protein A/G magnetic beads. Then, the RIP lysate was thawed quickly and incubated with the bead–antibody complex in RIP immunoprecipitation buffer. RNA-binding protein–RNA complexes were washed with RIP wash buffer. RNA was purified and analyzed using qRT-PCR.

Metabolite Measurements

Cells were cultured in 10 cm dishes, and those in the logarithmic growth phase were used for measurements of metabolites. Acetyl-CoA, acetate, and free fatty acid measurements were performed using an Acetyl-Coenzyme A Assay Kit (Sigma, MAK039), Acetate Colorimetric Assay Kit (Biovision, k658), and Total Cholesterol (T-CHO) Test Kit (Nanjing Jiancheng Bioengineering, A111-2-1), respectively. The detailed procedures are provided in Text S2.

Oil Red O Staining

Cells were inoculated on poly-l-lysine-coated cell slides and fixed with 10% neutral formaldehyde solution overnight. Tumor tissues were fixed, frozen, and sectioned into 10 μm slides. Cell or tissue slides were stained with Oil Red O and counterstained with hematoxylin. Lipid accumulation was visualized with an inverted microscope (Olympus, Japan).

Statistical Analysis

The results are presented as mean ± SD. The Student’s t-test was used to compare the differences between the two groups. The Wilcoxon test was used to assess SFTA1P levels in tumor and normal tissues and early-stage and advanced-stage tissues. The log-rank test was used to compare survival according to different SFTA1P levels. P < 0.05 was considered statistically significant.

Results

SFTA1P Is Identified in COE-Induced Malignant Transformation of Lung Epithelial Cells

To screen for differentially expressed lncRNAs during COE-induced malignant transformation, we performed high-throughput RNA sequencing using a malignant transformation cell model, which was induced by 20 μg/mL COE exposure for 120 days and verified with the characteristics of lung cancer (Figure A). A substantial difference in the lncRNA expression profiles was found, with the top 15 upregulated lncRNAs and the top 15 downregulated lncRNAs shown in Figure B. According to reported studies, we selected three lncRNAs (ENSG00000225383.2/SFTA1P, ENSG00000260051.1/AC031600, ENSG00000257647.1/AC124312) that showed significant differences and had few reports for validation. As shown in Figure C–E, consistent with the sequencing results, SFTA1P was significantly decreased in 16HBE-T compared to 16HBE, while AC031600 and AC124312 were increased. To screen for functional lncRNAs, we synthesized overexpression vectors targeting SFTA1P, AC031600, and AC124312 and transfected them into cells. CCK8 results showed that overexpression of SFTA1P could significantly inhibit cell growth, which is consistent with the cell phenotype caused by its low expression in 16HBE-T cells (Figure F). However, overexpression of AC031600 or AC124312 also inhibited cell growth, which is not consistent with the cell phenotype caused by their high expression in 16HBE-T cells (Figure G,H). We therefore focused on SFTA1P for further analysis.

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Identification of SFTA1P in COE-induced malignant cell transformation. (A) Schematic of the malignant transformation cell model induced by COE. (B) Heatmap showing the top 15 upregulated lncRNAs and top 15 downregulated lncRNAs in 16HBE-T cells compared to 16HBE cells. (C–E) Expression of SFTA1P (C), AC031600 (D), and AC124312 (E) in 16HBE and 16HBE-T cells. (F–H) Effects of transient overexpression of SFTA1P (F), AC031600 (G), and AC124312 (H) on cell proliferation. *P < 0.05 according to Student’s t-test.

COE-Related SFTA1P Is Expressed at Low Levels in Lung Cancer and Is Associated with Lung Cancer Patients’ Prognosis

To investigate the role of SFTA1P in COE-induced malignant transformation, we selected cells exposed to COE for 75 days as the intermediate stage of malignant transformation and analyzed SFTA1P expression at different stages of COE-induced malignant transformation. Interestingly, as the COE exposure duration increased, SFTA1P showed a gradient reduction in our RNA-seq data (Figure A) and qRT-PCR results (Figure B). We next investigated the expression of SFTA1P in LUSC tissues and normal tissues using the TCGA database. The results showed that SFTA1P expression was significantly lower in tumor tissues compared with that in normal tissues (Figure C). Moreover, we found that expression of SFTA1P was low in patients with an advanced stage compared with patients with an early stage (Figure D). Furthermore, we examined the relationship between SFTA1P expression and patient survival time. As shown in Figure E, low expression of SFTA1P was significantly correlated with short survival time in patients (HR, 0.63; 95%CI, 0.53–0.74; P = 3.5 × 10–08). To explore the potential mechanism for the low expression of SFTA1P in LUSC, we analyzed the genomic profiles of SFTA1P using the cBioPortal database and found a deep deletion of copy number in SFTA1P in LUSC (Figure F). Moreover, the survival time of patients with altered copy numbers was significantly lower than that of patients without altered copy numbers (Figure G). Interestingly, the measurement of RNA copy number per cell for SFTA1P showed that a significant deletion in COE was induced in 16HBE-T compared with 16HBE (Figure H). These results indicate that COE-induced downregulation of SFTA1P is attributed to copy number deletion and is associated with poor prognosis of patients.

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COE-related SFTA1P is expressed at low levels in LUSC tumor tissues due to loss of copy number. (A, B) SFTA1P expression was downregulated gradiently with increased COE exposure in our RNA-seq data (A) and qRT-PCR verification (B). 75COE indicates that the cells were exposed to COE for 75 days and were exposed every 2 days. (C, D) SFTA1P levels were significantly lower in LUSC tumors than in normal tissues (C) and in advanced-stage tumors than in early-stage tumors (D). Wilcoxon rank-sum tests (two-tailed) were used to determine P values. (E) Kaplan–Meier Plotter estimates of the survival time of patients using different SFTA1P levels in lung cancer. (F) Genomic profiles of SFTA1P were analyzed using the cBioPortal database. (G) Kaplan–Meier analysis of survival time in patients with different altered copy numbers of SFTA1P. (H) Copy number per cell of SFTA1P in 16HBE and 16HBE-T cells, as determined by qRT–PCR. P < 0.0001 according to Student’s t-test.

SFTA1P Is a Long Noncoding RNA Located in the Cytoplasm

To further annotate SFTA1P, we predicted the encoding ability of SFTA1P using CPAT (Coding Potential Assessment Tool, http://lilab.research.bcm.edu/cpat/index.php) and CPC (Coding Potential Calculator, http://cpc.cbi.pku.edu.cn) databases. The results showed that both database predictions indicated that SFTA1P has no protein-encoding ability (Figure A). Next, in order to study the functions of SFTA1P, we detected its localization in cells. The results showed that SFTA1P was mainly located in the cytoplasm using the Cytoplasmic and Nuclear Fractionation assays (Figure B,C) and RNA FISH assay (Figure D,E). All these results suggested that SFTA1P is a long noncoding RNA located in the cytoplasm.

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SFTA1P is located in the cytoplasm. (A) CPAT and CPC databases were used to predict the encoding ability of SFTA1P. (B–E) Subcellular location analysis by PCR (B, C) and RNA FISH (D, E) showed that SFTA1P is mainly located in the cytoplasm. U6 and 18S RNA were used as nuclear and cytoplasmic markers, respectively.

SFTA1P Inhibits Lung Cancer Cell Proliferation In Vitro and In Vivo

The effects of SFTA1P on cancer cell proliferation were investigated in vitro and in vivo by stable knockdown or overexpression of SFTA1P in cancer cells (Figure S1). The results showed that the knockdown of SFTA1P significantly increased the ability of H226, H1703, and 16HBE cells to proliferate and form colonies, while overexpression of SFTA1P substantially decreased the ability of H226, H1703, and 16HBE-T cells to proliferate and form colonies in vitro (Figure A–D). Similar results were also obtained from the in vivo assays: the growth rates of xenograft H226 and H1703 cells with stable knockdown of SFTA1P were significantly higher than those of control H226 and H1703 cells (Figure E). All these results strongly demonstrated that SFTA1P acts as an anticarcinogenic lncRNA that inhibits lung tumorigenesis in vitro and in vivo.

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SFTA1P inhibits the proliferation of LUSC cancer cells in vitro and in vivo. (A–C) Effects of SFTA1P knockdown (left panel) or overexpression (right panel) on the proliferation of H226 (A), H1703 (B), 16HBE, and 16HBE-T cells (C) using CCK8 assay. *P < 0.5, **P < 0.01, ***P < 0.001, ****P < 0.0001 according to Student’s t-test, n = 4. (D) Effects of SFTA1P knockdown (left panel) or overexpression (right panel) on colony formation of H226 (upper panel), H1703 (middle panel), and 16HBE, 16HBE-T (lower panel). (E) Effect of SFTA1P expression change on LUSC xenograft growth in mice. Images of the subcutaneous xenografts at the end of the experiments (left panels) and the growth curves of the xenografts (right panels) are shown. n = 5, ***P < 0.001 according to Student’s t-test.

SFTA1P Directly Interacts with ACSS2 and Leads to Abnormal Acetyl-CoA Metabolism

To further elucidate the mechanism by which SFTA1P inhibits the proliferation of lung cancer, we performed RNA pull-down assays using the SFTA1P sense probe and cell lysate from H226. Mass spectrometry identified 558 potential interacting proteins (Table S2). We ranked proteins according to Label-Free Quantification (LFQ) Intensity and selected 3 potential proteins (SRSF7, SNRPE, ACSS2) with unique peptides greater than 2 from the top 15 for western blot validation. The results showed that only ACSS2 interacted with SFTA1P (Figure A). Furthermore, the RIP assay using antibodies against ACSS2 verified the specific interaction between SFTA1P and ACSS2 (Figure B). Computational RNA-protein docking analysis further supported the interaction between SFTA1P and ACSS2 (Figure C, confidence score = 0.9570, http://hdock.phys.hust.edu.cn). ACSS2 is an enzyme that catalyzes the synthesis of acetyl-CoA from acetate (Figure D). The binding sites of SFTA1P and ACSS2 were predicted using PRIdictor. Prediction scores >0.5 were considered binding sites. The results showed that there were 7 SFTA1P binding sites in the ACSS2 protein, 6 of which were located in the active region (Figure E,F). All of these findings indicated that SFTA1P may affect the activity of ACSS2 by binding to the enzyme’s active region.

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SFTA1P inhibits the synthesis of acetyl-CoA. (A) Western blot analysis of proteomic screening suggested 3 potential SFTA1P-binding proteins (ACSS2, SNRPE, SRSF7) obtained from the RNA pull-down assay. (B) Association of ACSS2 with SFTA1P was determined using the RIP assay. (C) 3D image shows the interaction between SFTA1P and ACSS2. (D) Diagram of cellular acetyl-CoA metabolism in mammalian cells. (E) Structural domain of ACSS2. (F) Prediction binding scores of SFTA1P and ACSS2. (G, H) Effect of SFTA1P expression change on the acetyl-CoA level (H226-sh-SFTA1P-1 vs H226-sh-Control, FC = 1.6; H226-sh-SFTA1P-2 vs H226-sh-Control, FC = 1.4; H226-SFTA1P vs H226-Control, FC = 0.7; H1703-sh-SFTA1P-1 vs H1703-sh-Control, FC = 1.4; H1703-sh-SFTA1P-2 vs H1703-sh-Control, FC = 1.4; H1703-SFTA1P vs H1703-Control, FC = 0.8). (I) Acetyl-CoA levels in the 16HBE and 16HBE-T cells (16HBE-T vs 16HBE, FC = 1.5). (J, K) Effect of SFTA1P expression change on the acetate level (H226-sh-SFTA1P-1 vs H226-sh-Control, FC = 0.5; H226-sh-SFTA1P-2 vs H226-sh-Control, FC = 0.6; H226-SFTA1P vs H226-Control, FC = 1.2; H1703-sh-SFTA1P-1 vs H1703-sh-Control, FC = 0.8; H1703-sh-SFTA1P-2 vs H1703-sh-Control, FC = 0.7; H1703-SFTA1P vs H1703-Control, FC = 1.3). (L) Acetate levels in the 16HBE and 16HBE-T cells (16HBE-T vs 16HBE, FC = 0.6). P values according to Student’s t-test, n = 3.

Next, we measured the acetyl-CoA and acetate levels in H226 and H1703 cells with stable knockdown or overexpression of SFTA1P. The results showed that knockdown of SFTA1P significantly increased the acetyl-CoA level and decreased the acetate level, while overexpression of SFTA1P substantially decreased the acetyl-CoA level and increased the acetate level (Figure G,H,J,K). Interestingly, the acetyl-CoA level was increased in the malignant transformation cell 16HBE-T compared with the normal cell 16HBE (Figure I), while it was reversible at the acetate level (Figure L). Acetyl-CoA is an important hub in biochemical metabolism and is a raw material for synthesizing fatty acids and cholesterol. Next, we measured fatty acid and cholesterol levels in H226 and H1703 cells with different expression levels of SFTA1P. Consistent with the acetyl-CoA levels, knockdown of SFTA1P significantly increased the fatty acid and cholesterol levels, while overexpression of SFTA1P substantially decreased fatty acid (Figure A,B) and cholesterol levels (Figure D,E). Moreover, fatty acid and cholesterol levels were significantly higher in 16HBE-T than in 16HBE (Figure C,F). Furthermore, Oil red O staining showed that knockdown of SFTA1P promoted the formation of lipid droplets, while overexpression of SFTA1P inhibited the formation of lipid droplets in the H226 and H1703 cells in vitro (Figure G). Interestingly, consistent with in vitro results, we found that the knockdown of SFTA1P promoted the formation of lipid droplets in vivo (Figure H). All these results strongly demonstrated that SFTA1P interacted with ACSS2 to affect its enzyme activity of ACSS2 and lead to abnormal acetyl-CoA metabolism in COE-induced malignant transformation.

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SFTA1P inhibits acetyl-CoA metabolism. (A, B) Effect of SFTA1P expression change on the fatty acid level (H226-sh-SFTA1P-1 vs H226-sh-Control, FC = 1.4; H226-sh-SFTA1P-2 vs H226-sh-Control, FC = 1.6; H226-SFTA1P vs H226-Control, FC = 0.5; H1703-sh-SFTA1P-1 vs H1703-sh-Control, FC = 1.3; H1703-sh-SFTA1P-2 vs H1703-sh-Control, FC = 1.5; H1703-SFTA1P vs H1703-Control, FC = 0.7). (C) Fatty acid levels in 16HBE and 16HBE-T (16HBE-T vs 16HBE, FC = 1.5). (D, E) Effect of SFTA1P expression change on th cholesterol level (H226-sh-SFTA1P-1 vs H226-sh-Control, FC = 1.6; H226-sh-SFTA1P-2 vs H226-sh-Control, FC = 1.5; H226-SFTA1P vs H226-Control, FC = 0.7; H1703-sh-SFTA1P-1 vs H1703-sh-Control, FC = 1.2; H1703-sh-SFTA1P-2 vs H1703-sh-Control, FC = 1.3; H1703-SFTA1P vs H1703-Control, FC = 0.8). (F) Cholesterol levels in 16HBE and 16HBE-T cells (16HBE-T vs 16HBE, FC = 1.5). P values according to Student’s t-test, n = 3. (G) Representative images of Oil Red O staining of H226 and H1703 cells with SFTA1P silencing and overexpression. (H) Representative images of Oil Red O staining in subcutaneous xenografts with SFTA1P silencing.

SFTA1P Inhibits Lung Cancer Malignancy through Acetyl-CoA Metabolic Remodeling

To further validate the phenotypic changes caused by abnormal acetyl-CoA metabolism regulated by SFTA1P, we transiently transfected ACSS2 into H226, H1703, and 16HBE-T cells with overexpression of SFTA1P. CCK8 and colony formation assay results showed that transfection of ACSS2 in cells with overexpression of SFTA1P could significantly rescue the phenotype caused by SFTA1P (Figure A–D). All of these results strongly support that SFTA1P inhibited lung cancer malignancy through acetyl-CoA metabolic remodeling.

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Consequences of ACSS2 overexpression in cell malignancy. (A–C) Proliferation activities of LUSC cells with overexpression of SFTA1P and ACSS2 using CCK8 assay. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 according to Student’s t-test, n = 4. (D) Colony formation of LUSC cells with overexpression of SFTA1P and ACSS2.

Discussion

In the present study, we have identified a long noncoding RNA, SFTA1P, which was downregulated in COE-induced malignant transformation. Aberrant overexpression of SFTA1P in lung cancer cells could significantly inhibit lung cancer malignancy. Here, we show that SFTA1P may directly interact with ACSS2, an important enzyme that promotes the synthesis of acetyl-CoA, leading to the abnormal metabolism of acetyl-CoA and reducing the synthesis of fatty acids and cholesterol, thus inhibiting the malignant phenotype of lung cancer cells. Indeed, we also found that patients with high expression of SFTA1P had a better prognosis than those with low expression of SFTA1P. These results elucidate the molecular mechanism underlying the antioncogenic role of COE-related lncRNAs in lung cancer and provide a scientific basis for the early prevention and diagnosis of COE-caused occupational lung cancer.

SFTA1P is a known pseudogene-derived lncRNA. Studies have reported that SFTA1P is abnormally expressed in many cancers and plays different biological functions in different types of cancer. , In cervical cancer, SFTA1P promoted tumorigenesis and tumor progression. Conversely, SFTA1P was downregulated in gastric cancer and lung adenocarcinoma compared with normal tissues and suppressed cell proliferation, migration, and invasion. , In LUSC, SFTA1P was significantly associated with patients’ prognosis. Moreover, SFTA1P promoted apoptosis and increased cisplatin chemosensitivity in LUSC. All of these previous findings indicate that SFTA1P may be an important player in cancer development. In the present study, we found that SFTA1P expression was downregulated in COE-induced malignant transformation. This result is consistent with a previous study that showed that SFTA1P was downregulated in LUSC tissue. However, our study is the first to reveal the relationship between SFTA1P and environmental pollutants. Moreover, we found a deep deletion of the copy number of SFTA1P in LUSC. Interestingly, the survival time of patients with altered copy numbers was significantly lower than that of patients without altered copy numbers. SFTA1P could suppress LUSC cell proliferation in vitro and in vivo. These results strongly support our conclusion that abnormally low expression of SFTA1P may function as an important player that promotes the COE-induced malignant transformation of cells.

lncRNAs are functional units due to their lack of ability to encode proteins. Increasing evidence suggests that the subcellular location of lncRNAs is crucial to their function. − In our cytoplasmic and nuclear fractionation assays and RNA FISH assay, we found that SFTA1P was mainly located in the cytoplasm, which indicates that SFTA1P may bind to RNA-binding proteins (RBPs) or act as a sponge to regulate target gene expression by absorbing microRNAs. Furthermore, RNA pull-down and RIP assays identified that SFTA1P may interact with ACSS2. ACSS2 is a member of the acetyl-CoA synthetase short-chain family and is responsible for synthesizing acetyl-CoA from acetate. It is located in the cytoplasm and nucleus. Among these, cytosolic ACSS2 is crucial for maintaining the growth of tumor cells under hypoxic conditions, while nuclear ACSS2 plays an important role in histone acetylation and regulates gene expression. − All of these strongly suggest that SFTA1P may regulate acetyl-CoA production by interacting with ACSS2. Interestingly, this strongly supports our hypothesis. We found that the level of acetyl-CoA was significantly increased and acetate was significantly decreased with the knockdown of SFTA1P, while acetyl-CoA was substantially decreased and acetate was increased with the overexpression of SFTA1P.

Acetyl-CoA is a key intermediate product of cell metabolism and a hub to connect protein, sugar, and lipid metabolism. , It is mainly produced from nutrient catabolism to provide fuel for the tricarboxylic acid cycle and is an important building block for fatty acid biosynthesis. Substantial evidence indicates that acetyl-CoA is an important player in tumorigenesis. , Normally, acetyl-CoA mainly comes from the oxidative decarboxylation of pyruvic acid. , However, the Warburg effect indicates that tumor cells mainly carry out aerobic glycolysis, and pyruvic acid produced in this process is converted into lactic acid, which is transported extracellularly. Therefore, tumor cells cannot produce acetyl-CoA through oxidative decarboxylation but rely on cytosolic ACSS2. In metabolic stress, ACSS2 promoted acetate utilization and contributed to cancer cell growth. miR-15a-5p inhibited ACSS2-mediated acetyl-CoA activity and histone acetylation to inhibit lipid metabolism, thereby inhibiting the metastasis of lung cancer cells. All these findings strongly suggest that SFTA1P may affect COE-induced malignant transformation by regulating acetyl-CoA metabolism. As shown in our study, we found that fatty acid and cholesterol levels were significantly increased in cells with knockdown of SFTA1P, and decreased in cells with overexpression of SFTA1P. Moreover, we transfected ACSS2 into SFTA1P overexpression cells and found that ACSS2 could rescue SFTA1P-induced cell phenotype. These novel findings have led to the significant conclusion that SFTA1P inhibits lung cancer malignancy through acetyl-CoA metabolic remodeling.

In summary, the present study identified a significant association between COE-induced malignant transformation and low expression of SFTA1P. Mechanistic analysis demonstrated that COE induced the downregulation of SFTA1P, which led to the reprogramming of acetyl-CoA metabolism by interacting with ACSS2, thereby promoting the occurrence of lung cancer. These findings provide an important theoretical basis for the prevention of lung cancer and the search for early diagnostic biomarkers.

Supplementary Material

eh5c00524_si_001.pdf (208.6KB, pdf)
eh5c00524_si_002.xlsx (66.3KB, xlsx)

Acknowledgments

This research was supported by the National Natural Science Foundation of China (Grant No. 82173495, 82203761, 82574134) and the Natural Science Foundation of Shandong Province (Grant No. ZR2024MH133).

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/envhealth.5c00524.

  • Qualitative analysis of proteins by mass spectrometry; metabolite measurements; validation of stable knockdown and stable overexpression efficiency of SFTA1P; primer sequences used in this study (PDF)

  • Proteins interacted with SFTA1P identified by mass spectrometry (Table S2) (XLSX)

∥.

Q.J. and X.L. contributed equally to this work.

The authors declare no competing financial interest.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

eh5c00524_si_001.pdf (208.6KB, pdf)
eh5c00524_si_002.xlsx (66.3KB, xlsx)

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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