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. (C) 2018 Elsevier Inc. All rights reserved.