Published on May 7, 2019 in Biochem Biophys Res Commun volume 512(3).

PubMed ID: 30905413

DOI: S0006-291X(19)30482-6


Abstract:

Lung cancer is one of the leading causes of cancer-related death in developedcountries. Despite decades of intensive efforts to comate this malignant disease,the prognosis of lung cancer remains unfavorable and is especially poor in advancednon-small cell lung cancer (NSCLC). However, whether and how the m6A demethylase FTOfunctions in lung cancer cells remain unknown. Here in the present study, we showthat FTO plays an oncogenic role in human NSCLC. FTO mRNA and protein levels wereoverexpressed in human NSCLC tissues and cell lines, which was associated with thereduced m6A content. We next knocked down FTO expression in human lung cancer celllines with lentivirus-mediated shRNAs and the cellular proliferation assaydemonstrated that FTO loss-of-function reduced the proliferation rate of cancercells. FTO knockdown also inhibited the colony formation ability of lung cancercells. Importantly, our xenograft experiment showed that FTO knockdown reduced lungcancer cells growth in vivo. Mechanism analysis demonstrated that FTO decreased them6A level and increased mRNA stability of ubiquitin-specific protease (USP7), whichwas relied on the demethylase activity of FTO. USP7 mRNA level was overexpressed inhuman lung cancer tissues and USP7 expression was positively correlated with FTOmRNA level. Genetic knockdown or pharmacological inhibition (P5091 or P22027) ofUSP7 reduced the proliferation rate of lung cancer cells and decreased the capacityof colony formation of lung cancer cells in vitro, whereas lung cancer cells growthinhibition by FTO knockdown is restored by overexertion of USP7. Collectively, ourfindings demonstrate that the m6A demethylase FTO promotes the growth of NSCLC cellsby increasing the expression of USP7.CI - Copyright © 2019 Elsevier Inc. All rights reserved.



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