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N 6 -Methyladenosine (m 6 A) represents the most prevalent internal modification in mammalian mRNAs. Emerging evidences suggest that m 6 A modification is profoundly implicated in many biological processes, including cancer development. However, limited knowledge is available about the functional importance of m 6 A 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 m 6 A modification genes including METTL3, METTL14 and ALKBH5, was the major dysregulated factor responsible for aberrant m 6 A 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 m 6 A 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., (Copyright © 2018 Elsevier Inc. All rights reserved.)