m6A demethylase FTO facilitates tumor progression in lung squamous cell carcinoma by regulating MZF1 expression

Highlights: • The prognostic value of m⁶A methyltransferase and demethylase in lung cancer. • Differentially expressed FTO accounts for the aberrant m⁶A modification in LUSC. • FTO acts as an oncogene in LUSC. • MZF1 mediates FTO regulation in LUSC. N⁶-Methyladenosine (m⁶A) represents the most prevalent internal modification in mammalian mRNAs. Emerging evidences suggest that m⁶A modification is profoundly implicated in many biological processes, including cancer development. However, limited knowledge is available about the functional importance of m⁶A in lung cancer. In this study, by data mining The Cancer Genome Atlas (TCGA) database, we first identified fat mass- and obesity-associated protein (FTO) as a prognostic factor for lung squamous cell carcinoma (LUSC). Then we showed that FTO, but not other m⁶A modification genes including METTL3, METTL14 and ALKBH5, was the major dysregulated factor responsible for aberrant m⁶A modification in LUSC. Loss-of-function studies suggested that FTO knockdown effectively inhibited cell proliferation and invasion, while promoted cell apoptosis of L78 and NCI-H520 cells. Furthermore, overexpression of FTO, but not its mutant form, facilitated the malignant phenotypes of CHLH-1 cells. Mechanistically, FTO enhanced MZF1 expression by reducing m⁶A levels and mRNA stability in MZF1 mRNA transcript, leading to oncogenic functions. Taken together, our study demonstrates the functional importance of FTO in the tumor progression of LUSC and provides a potential therapeutic target for LUSC treatment.