FTO Mediates the Tobacco Carcinogen NNK-Induced Beas-2B Cells Malignant Transformation via the DIXDC1/PI3K/AKT Signaling Axis.

Cigarette smoking is a primary etiological factor in lung cancer, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a prototypical tobacco-specific nitrosamine carcinogen. Although FTO has been implicated in the progression of various cancers, its specific role in smoking-associated lung carcinogenesis remains incompletely understood. In this study, we built a model of NNK-induced malignant transformation of human bronchial epithelial Beas-2B cells (designated Beas-2B-NNK cells) to explore the function and regulatory mechanism of FTO during NNK-induced lung carcinogenesis. Through quantitative real-time PCR (RT-qPCR) assays, FTO levels were found to be notably higher in Beas-2B-NNK cells when compared with their parental Beas-2B cell line. Then, knocking down FTO expression using short hairpin RNA (shRNA) led to marked repression of proliferation, migration, and cell-cycle progression in Beas-2B-NNK cells. Bioinformatics analysis revealed a positive correlation between FTO and DIXDC1, and when FTO was knocked out, the sharpest drop in DIXDC1 expression was seen in Beas-2B-NNK cells. Combined bioinformatic and Western blot analysis observed that DIXDC1 regulates the malignant transformation of Beas-2B-NNK cells via the PI3K/AKT signaling pathway. In summary, these findings suggest that FTO participates in NNK-induced malignant transformation of Beas-2B cells via the DIXDC1/PI3K/AKT signaling axis.