The RNA-editing enzyme ADAR promotes lung adenocarcinoma migration and invasion by stabilizing FAK

Large-scale, genome-wide studies report that RNA binding proteinsare altered in cancers, but it is unclear how these proteins control tumor progression. We found that the RNA-editingprotein ADAR( adenosine deaminaseacting on double-stranded RNA) acted as a facilitator of lung adenocarcinoma (LUAD) progression through its ability to stabilize transcripts encoding focal adhesionkinase (FAK). In samples from 802 stage I LUAD patients, increased abundance of ADARat both the mRNA and protein level correlated with tumor recurrence. Knocking down ADARin LUAD cells suppressed their mesenchymal properties, migration, and invasion in culture. Analysisof gene expression patterns in LUAD cells identified ADAR-associated enrichment of a subset of genes involved in cell migration pathways; among these, FAK is the most notable gene whose expression was increased in the presence of ADAR. Molecular analyses revealed that ADARposttranscriptionally increased FAK protein abundance by binding to the FAK transcript and editing a specific intronic site that resulted in the increased stabilization of FAK mRNA. Pharmacological inhibition of FAK blocked ADAR-induced invasiveness of LUAD cells, suggesting a potential therapeutic application for LUAD that has a high abundance of ADAR.