Long non-coding RNA NEAT1 regulates ferroptosis sensitivity in non-small-cell lung cancer

Abstract

Objectives Ferroptosis is caused by iron-dependent lipid peroxide accumulation, the sensitivity of which might be regulated by acyl-CoA synthetase long chain family member 4 (ACSL4). Non-small-cell lung cancer (NSCLC) can resist oxidative stress and reduce the sensitivity of tumor cells to ferroptosis by changing the expression of some proteins. Mechanisms involving ferroptosis sensitivity in NSCLC are not fully understood. Methods A dual-luciferase reporter assay was used to confirm a targeting relationship between long non-coding (lnc)RNA NEAT1 and ACSL4. Overexpression and silencing assays of NEAT1 function were used to determine its roles in cell death (by TUNEL staining) and lipid peroxidation (by malondialdehyde levels). Expression of ferroptosis-related proteins (SLCA11, GPX4, and TFR4) was evaluated by western blot in NSCLC cells treated or not with the ferroptosis inducer erastin. Results Erastin-induced cell death was positively correlated with ACSL4 level. NEAT1 regulated levels of ACSL4 and proteins related to the ferroptosis and classical apoptosis pathways. Levels of ACSL4, SLC7A11, and GPX4 were decreased more by NEAT1 silencing plus erastin than by erastin alone. Conclusion NEAT1 regulates ferroptosis and ferroptosis sensitivity, with the latter depending on ACSL4, suggesting that targeting NEAT1 or ACSL4 may be a viable therapeutic approach to the treatment of NSCLC.

Identification of Ferroptosis-Related Long Noncoding RNA and Construction of a Novel Prognostic Signature for Gastric Cancer

“…Recent reports suggest that ferroptosisrelated lncRNAs play important roles in tumorigenesis, progression, and metastasis via multiple mechanisms. Wu et al [7] reported that lncRNA NEAT1 promoted ferroptosis and ferroptosis sensitivity in non-small-cell lung cancer by regulating the expression of ACSL4. Qi et al [8] reported that lncRNA GABPB1-AS1 could induce ferroptosis in hepatocellular carcinoma cells by inhibiting the translation of GABPB1.…”

A Novel Ferroptosis-Related Long Non-coding RNA Prognostic Risk Model for Gastric Cancer

“…Moreover, lncRNAs may affect ferroptosis in various ways, and it has been reported that lncRNA GABPB1-AS1 in HCC leads to the downregulation of the gene encoding Peroxiredoxin-5 (PRDX5) peroxidase, suppression of cellular antioxidant capacity, eventual induction of ferroptosis, and high GABPB1-AS1 levels in patients with HCC, which correlated with improved OS (22). Wu et al (23) revealed that lncRNA NEAT1 regulates ferroptosis and ferroptosis sensitivity in non-small-cell lung cancer by targeting acyl-CoA synthetase long-chain family member 4 (ACSL4), which may regulate ferroptosis sensitivity. Seven ferroptosis-related lncRNA signatures were constructed in colon adenocarcinoma (COAD), and the prognostic value of these lncRNAs was con rmed in patients with COAD (24).…”

Close interactions between lncRNAs, lipid metabolism and ferroptosis in cancer

“…Overexpression of NEAT1 can inhibit the expression of ACSL4, increase the expression of SLC7A11 and GPX4, and reduce the content of regulatory iron in cells. Finally, the occurrence of ferroptosis is decreased, and cell apoptosis is inhibited [204].…”