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High-Fat Diet Impairs Ferroptosis and Promotes Cancer Invasiveness Via Downregulating Tumor Suppressor ACSL4 in Lung Adenocarcin

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High-Fat Diet Impairs Ferroptosis and Promotes Cancer Invasiveness Via Downregulating Tumor Suppressor ACSL4 in Lung Adenocarcin Zhang et al. Biology Direct (2021) 16:10 https://doi.org/10.1186/s13062-021-00294-7 RESEARCH Open Access High-fat diet impairs ferroptosis and promotes cancer invasiveness via downregulating tumor suppressor ACSL4 in lung adenocarcinoma Yixiang Zhang1, Songyu Li2, Fengzhou Li1, Changsheng Lv1* and Qing-kai Yang2* Abstract Background: Long-chain acyl-CoA synthetase-4 (ACSL4) is involved in fatty acid metabolism, and aberrant ACSL4 expression could be either tumorigenic or tumor-suppressive in different tumor types. However, the function and clinical significance of ACSL4 in lung adenocarcinoma remain elusive. Results: ACSL4 was frequently downregulated in lung adenocarcinoma when analyzing both the TCGA database and the validation samples, and the lower ACSL4 expression was correlated with a worse prognosis. Using gene set enrichment analysis, we found that high ACSL4 expression was frequently associated with the oxidative stress pathway, especially ferroptosis-related proteins. In vitro functional studies showed that knockdown of ACSL4 increased tumor survival/invasiveness and inhibited ferroptosis, while ACSL4 overexpression exhibited the opposite effects. Moreover, high-fat treatment could also inhibit erastin-induced ferroptosis by affecting ACSL4 expression. The anti-tumor effects of ferroptosis inducers and the anti-ferroptosis effects of the high-fat diet were further validated using the mouse xenograft model. Conclusions: ACSL4 plays a tumor-suppressive role in lung adenocarcinoma by suppressing tumor survival/ invasiveness and promoting ferroptosis. Our study provided a theoretical reference for the application of ferroptotic inducers and dietary guidance for lung adenocarcinoma patients. Keywords: Long-chain acyl-CoA synthetase-4, Ferroptosis, Lung adenocarcinoma, High-fat diet Background carbons as substrates [1], and ACSLs are also the response Long-chain acyl-CoA synthetase-4 (ACSL4), a member gene for peroxisome proliferator-activated receptor of the long-chain acyl-coenzyme synthetase (ACSL) fam- gamma (PPARγ), which mediates the lipid metabolism ily, is involved in the biosynthesis and catabolism of fatty and regulates caloric absorption [2]. The dysregulation of acids. There are five different isoenzymes in the ACSL ACSL4 is associated with a variety of lipid metabolism dis- family, ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6. eases. Different from other family members, ACSL4 ACSLs prefer fatty acids with chain lengths of 12 to 20 catalyzes the synthesis of arachidonic acid (AA) into ara- chidonic acid coenzyme A, which participates in the * Correspondence: [email protected]; [email protected] synthesis of membrane phospholipids. ACSL4 enriched 1Department of Thoracic Surgery, The First Affiliated Hospital of Dalian long polyunsaturated ω6 fatty acids in cell membranes Medicine University, No. 222 Zhongshan Road, Liaoning 116000 Dalian, and dictated ferroptosis sensitivity by shaping cellular lipid China 2Department of Oncology, Institute of Cancer Stem Cell, Dalian Medical composition [3, 4]. Ferroptosis, which is different from University, 9 Western Lvshun South Road, Liaoning 116044 Dalian, China © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhang et al. Biology Direct (2021) 16:10 Page 2 of 13 apoptosis and necrosis, is closely related to the disturb- cancer [19]. The prognostic value of ACSL4 in lung ance of iron-dependent lipid peroxides, and these accu- adenocarcinoma was determined by Kaplan-Meier ana- mulated lipid reactive oxygen species (L-ROS) could lead lysis using the Kaplan-Meier-plotter online software. to ferroptotic cell death. Previous studies found that in- ducers of ferroptosis could inhibit tumor growth and kill Gene set enrichment and pathway analysis cancer cells [5–7], and activation of ferroptosis becomes a To better understand the underlying molecular role of novel and effective way of cancer intervention. On the ACSL4 in lung adenocarcinoma, we further analyzed other hand, some studies showed that ACSL4 is associated data using TCGA database. The clinical and gene ex- with the development and progression of multiple cancers, pression data of 524 patients with lung adenocarcinoma including breast cancer [8, 9], colorectal cancer [10], and were obtained from TCGA (https://tcga-data.nci.nih. hepatocellular carcinoma [11]. As ACSL4 could exhibit ei- gov/tcga/). We used R software to perform molecular ther tumor-suppressive or tumor-promoting functions, it role analysis of TCGA database. Pathway enrichment is worth specifying the role of ACSL4 based on the spe- analyses were performed using gene set enrichment ana- cific cancer type, including lung adenocarcinoma where lysis (GSEA). Genes related to oxidative stress were se- ACSL4 is rarely studied. lected using the Gene Ontology (GO) database with the Lung adenocarcinoma is the main type of lung cancer search term ‘response to oxidative stress’ (http://www. and accounts for around 30 % of all newly diagnosed geneontology.org/). We explored the biological functions lung cancer worldwide [12]. Due to the early metastasis of the gene list and screened for genes involved in cellu- and recurrence of lung adenocarcinoma, the 5-year sur- lar oxidative stress. Patients were divided into high vival rate is below 30 % [13]. Identifying genes that are ACSL4 expression group (n = 262) and low ACSL4 ex- aberrantly expressed helps understanding the initiation pression group (n = 262), and the median ACSL4 expres- and progression of lung adenocarcinoma. In this study, sion level was used to separate the high and low we used the gene expression data from the TCGA data- expression of ACSL4 patients. Relationships between base to characterize the patient prognosis stratified ACSL4 expression levels and genes involved in cellular based on ACSL4 expression and understand the ACSL4- oxidative stress were displayed as a heat map. The related pathways in lung adenocarcinoma. Furthermore, KEGG pathway database was a collection of manually we investigated the cellular function of ACSL4 and its drawn pathway maps of molecular interactions. To clar- impact on ferroptosis using in vitro cell line models. ify the regulatory relationship between ACSL4 expres- Lastly, we studied the effect of the high-fat diet on sion and ferroptosis-related gene expression. Pathway erastin-induced ferroptosis using both cell line and network analysis was based on the signal pathway of fer- mouse xenograft models. roptosis in the KEGG database, and the interaction net- work diagram of pathway research was constructed Methods ( https://www.genome.jp/keggbin/show_ Database analysis for ACSL4 expression and patient pathway?map04216). prognosis We used GEPIA to analyze ACSL4 expression and Antibodies and other reagents evaluate its relation to cancer patient survival. GEPIA Primary antibodies against ACSL4 and β-actin were pur- was an interactive web server for estimating the mRNA chased from Proteintech (Hubei Province, China). expression data from 9,736 tumors and 8,587 normal Erastin, a compound that could induce ferroptosis in samples in the Cancer Genome Atlas (TCGA) and mammalian cells, was purchased from Invitrogen Genotype-Tissue Expression (GTEx) dataset projects (California, USA). The SP-900 general immunohisto- (http://gepia.cancer-pku.cn/)[14–18]. The expression of chemical kit was purchased from ZSGB-BIO (Beijing, ACSL4 in 33 types of cancers and the matched normal China). Cell/tissue protein extraction kits were pur- samples was identified from the GEPIA database. The chased from Tiangen Biotech (Beijing, China). Other mRNA expression in cancer tissue compared to normal chemicals and reagents such as MTT, sodium dodecyl tissue was obtained, and P < 0.01 and |Log2FC|>1 were sulfate, Acryl&Bis premixed powder, BCA protein quan- set as the screening criteria for differentially expressed tification kit, and horseradish peroxidase (HRP) sub- genes. The expression profiles of ACSL4 isoforms in dif- strate luminescent solution were purchased from Sigma ferent types of cancers were identified and presented as (St. Louis, MO, USA), Vetec (St. Louis, MO, USA) and boxplots. Biological Industries (Kibbutz Beit Haemek, Israel). The Kaplan-Meier Plotter (http://kmplot.com)isan online database that comprises gene expression informa- Cell culture and tissue samples tion and clinical outcome parameters of breast cancer, In order to investigate the functional changes of ACSL4, lung cancer, liver cancer, ovarian cancer, and gastric experiments were performed with lung adenocarcinoma
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