<p>FTO Facilitates Lung Adenocarcinoma Cell Progression by Activating Cell Migration Through mRNA Demethylation</p>

Abstract

These authors contributed equally to this workBackground: The fat mass and obesity-associated protein (FTO) was identified as a critical demethylase involved in regulating cellular mRNA stability by removing N6methyladenosine (m6A) residues from mRNA. Emerging evidence has revealed that FTO is deeply implicated in lung cancer. However, knowledge of the function of FTO in lung adenocarcinoma (LUAC) is limited. Methods: FTO and FTO R96Q (R96Q), an FTO missense mutant lacking demethylase activity, were ectopically overexpressed, and FTO was knocked down via siRNA in A549 and H1299 cells. The relationships between FTO with cell characteristics and mRNA m6A levels were explored. Furthermore, RNA sequencing was performed on A549 cells. Results: FTO overexpression enhanced the proliferation, migration, and invasion ability of A549 and H1299 cells, decreased mRNA m6A levels. Interestingly, overexpression of R96Q, blunted the effects of FTO overexpression on cell proliferation and invasion. Through RNA sequencing analysis of A549 cells overexpressing FTO or R96Q and control A594 cells, 45 genes were identified as affected by m6A mRNA demethylation. Most of these genes were related to lung cancer, such as laminin γ2, thrombospondin 1, nerve growth factor inducible, integrin alpha11, and proprotein convertase subtilisin/kexin type 9. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses suggested that these genes are fundamental to cancer development processes, such as cell migration and extracellular matrix organization. Conclusion: Our research shows that FTO facilitates LUAC cell progression by activating cell migration through m6A demethylation; however, further research on the mechanism underlying FTO activity in LUAC is necessary.

The m6A RNA Demethylase ALKBH5 Promotes Radioresistance and Invasion Capability of Glioma Stem Cells

“…In addition, controversial results have been published in lung cancers. Whereas Jin et al showed that ALKBH5 expression decreases tumor growth and metastasis by reducing YAP expression [ 62 ], other authors reported an increase in proliferation and invasion of lung cancer cells mediated by ALKBH5 or FTO [ 18 , 19 , 22 ].…”

“…In addition, the involvement of RNA demethylases in cancer cell invasion remains controversial and has been reported by few studies. In breast, lung, and gastric carcinomas, the overexpression of ALKBH5 or FTO have been shown to promote cell invasion [ 18 , 19 , 20 , 21 , 22 ]. On the contrary, m6A RNA methylation could facilitate cell migration in other cancers, including, prostate, pancreas, colon, or hepatic cancers [ 23 , 24 , 25 , 26 ].…”

m6A RNA Methylation Regulators Participate in the Malignant Progression and Have Clinical Prognostic Value in Lung Adenocarcinoma

“…Especially, it has been demonstrated that several m6A methyltransferase, such as METTL3 and YTHDF1, facilitate lung adenocarcinoma progression by activating cell migration and invasion through m6A methylation ( Lin et al, 2016 ; Shi et al, 2019 ). While FTO and ALKBH5 affect the proliferation and invasion of lung adenocarcinoma cells via regulating multiple target genes and signaling pathways which are related to malignant tumors ( Chao et al, 2020 ; Ding et al, 2020 ). The above studies have confirmed our present results to some extent that m6A RNA methylation regulators participate in the malignant progression of lung adenocarcinoma.…”

Construction of a m6A RNA Methylation Regulator-related Signature for Prognosis and Immune Response in Lung Adenocarcinoma

“…Therefore, seeking for a robust prognostic signature to distinguish high-risk from low-risk patients and a nomogram to predict each patient's survival probability, is essential for determining the optimum therapeutic strategies and reversing the adverse prognosis for lung ADC patients. Accumulating evidence proved that abnormal m6A RNA methylation modi cations were intimately related to the pathogenesis and development of various cancers [11,23,29,31,[45][46][47], whereas the studies investigating their role in lung ADC are few. In this study, we discovered a signi cantly abnormal expression of m6A regulator genes in lung ADC.…”