High-fat diet impairs ferroptosis and promotes cancer invasiveness via downregulating tumor suppressor ACSL4 in lung adenocarcinoma

Yixiang Zhang,Songyu Li,Fengzhou Li,Changsheng Lv,Qing-Kai Yang

doi:10.1186/s13062-021-00294-7

Yixiang Zhang, Songyu Li + Show 3 more

Open Access

https://doi.org/10.1186/s13062-021-00294-7

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Abstract

BackgroundLong-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.ResultsACSL4 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.ConclusionsACSL4 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.

Highlights

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
ACSL4 was frequently downregulated and patients with low expression had a poor prognosis in lung adenocarcinoma We firstly assessed ACSL4 expression among 33 different types of cancers using the the Cancer Genome Atlas (TCGA) database, and several cancers demonstrated statistically significant differences in the ACSL4 expression level when compared with the corresponding normal control samples
(See figure on previous page.) Fig. 2 Low ACSL4 expression was associated with poor prognosis in lung adenocarcinoma. a The expression of ACSL4 in lung adenocarcinoma tissues and matched normal tissues was detected using Western blot

Summary

Introduction

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. The function and clinical significance of ACSL4 in lung adenocarcinoma remain elusive. Long-chain acyl-CoA synthetase-4 (ACSL4), a member of the long-chain acyl-coenzyme synthetase (ACSL) family, is involved in the biosynthesis and catabolism of fatty acids. ACSLs prefer fatty acids with chain lengths of 12 to 20. Some studies showed that ACSL4 is associated with the development and progression of multiple cancers, including breast cancer [8, 9], colorectal cancer [10], and hepatocellular carcinoma [11]. As ACSL4 could exhibit either tumor-suppressive or tumor-promoting functions, it is worth specifying the role of ACSL4 based on the specific cancer type, including lung adenocarcinoma where ACSL4 is rarely studied

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