LncRNA GABPB1-AS1 and GABPB1 regulate oxidative stress during erastin-induced ferroptosis in HepG2 hepatocellular carcinoma cells

Abstract

Ferroptosis is a non-apoptotic, iron-dependent oxidative form of cell death that is specifically induced by erastin in RAS mutant cancer cells. Ferroptotic cell death is the result of membrane lipid peroxide damage caused by the accumulation of hydroxyl radicals derived from H2O2 by the Fenton reaction. Peroxidases are key cellular antioxidant enzymes that block such damaging processes. Few studies have examined the roles of long non-coding RNAs (lncRNAs) in the regulation of cellular oxidative stress, especially in ferroptosis. Here, we demonstrated that erastin upregulated the lncRNA GABPB1-AS1, which downregulated GABPB1 protein levels by blocking GABPB1 translation, leading to the downregulation of the gene encoding Peroxiredoxin-5 (PRDX5) peroxidase and the eventual suppression of the cellular antioxidant capacity. Such effects critically inhibited the cellular antioxidant capacity and cell viability. Additionally, high expression levels of GABPB1 were correlated with poor prognosis of hepatocellular carcinoma (HCC) Patients, while high GABPB1-AS1 levels in HCC patients correlated with improved overall survival. Collectively, these data demonstrate a mechanistic link between GABPB1 and its antisense lncRNA GABPB1-AS1 in erastin-induced ferroptosis and establish GABPB1 and GABPB1-AS1 as attractive therapeutic targets for HCC.

The interaction between ferroptosis and lipid metabolism in cancer

“…4 Furthermore, erastin can upregulate the long noncoding RNA GABPB1-AS1, which downregulates GABPB1 protein levels by blocking GABPB1 translation, leading to the reduction of peroxiredoxin-5 peroxidase and the eventual suppression of cellular antioxidant capacity. 36 Cell death induced by RSL3 shares similar features with ferroptosis induced by erastin, i.e. a nonapoptotic, MEK-dependent, and iron-dependent oxidative cell death.…”

Oxidative Damage and Antioxidant Defense in Ferroptosis

“…The synthesis of antioxidants, such as glutathione (GSH), coenzyme Q10 (CoQ10) and tetrahydrobiopterin (BH 4 ), is the main defense strategy in the process of ferroptosis, which is related to multiple enzymes or proteins (Figure 1). In addition to the antioxidant systems discussed below, some antioxidant proteins, such as peroxiredoxins (PRDXs) (Lu et al, 2019;Qi et al, 2019;Lovatt et al, 2020) and thioredoxin (Llabani et al, 2019), can also block ferroptotic cell death. Therefore, an integrated antioxidant defense network exists in different cells.…”

Novel insights on targeting ferroptosis in cancer therapy

“…Long non-coding RNAs (LncRNAs) have important roles in ferroptosis. For instance, lncRNA GABPB1-AS1 can down-regulate the GABPB1 level and inhibit its Zhang, K et al [84] Inhibit the expression of TFR1 Reduce the accumulation of Glu Decrease the depletion of Glu antioxidant capacity, thereby inducing ferroptosis in hepatic cancer cells [77].…”