FOXA2 enhances anoikis sensitivity in lung adenocarcinoma cells: Dual role of ABCA8 upregulation and NOX4 suppression

Within the present study, the aim was to investigate the detailed mechanism of forkhead box protein A2 (FOXA2) in anoikis resistance in lung adenocarcinoma (LUAD). The levels of FOXA2 and ATP‑binding cassette subfamily A member 8 (ABCA8) were assessed using public databases. The effects of overexpression (oe)‑FOXA2, oe‑nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and sh‑ABCA8 on NOX4 levels, aggregation, cell viability, apoptosis and apoptosis‑related proteins were analyzed using reverse transcription quantitative PCR, microscopy, MTT assays, flow cytometry and western blotting. Chromatin immunoprecipitation and dual‑luciferase reporter assays were employed to determine the interaction between FOXA2 and ABCA8. In LUAD, FOXA2 and ABCA8 mRNA levels were downregulated, with lower expression observed in in A549 cells compared with BEAS‑2B cells; this pattern was pronounced under suspension culture, where A549 cells showed a further decrease in FOXA2/ABCA8 expression alongside a marked increase in NOX4 expression, compared with adherent culture. Furthermore, oe‑ABCA8 inhibited NOX4 expression and reversed the effects of oe‑NOX4 on enhancing cell aggregation, promoting cell viability, decreasing apoptosis, suppressing cleaved caspase‑3 expression and increasing NOX4 level in suspended A549 cells. Furthermore, FOXA2 bound to the ABCA8 promoter region and oe‑FOXA2 reversed the effects of ABCA8 silencing on suspended A549 cells, including enhanced cell aggregation, increased cell viability, reduced apoptosis, suppressed cleaved caspase‑3 expression and elevated NOX4 expression. Collectively, FOXA2 enhanced ABCA8 transcription, leading to inhibition of NOX4 expression and subsequently alleviating anoikis resistance in A549 cells.