Research ArticleCancer

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

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Sci. Signal.  19 Sep 2017:
Vol. 10, Issue 497, eaah3941
DOI: 10.1126/scisignal.aah3941

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Metastatic edits to FAK

Drugs that inhibit cell migration pathways, such as that mediated by the kinase FAK, may prevent metastasis and improve long-term survival in cancer patients. Amin et al. found that the RNA-editing enzyme ADAR supports the activity of FAK. In lung adenocarcinoma cells, ADAR bound to and edited FAK mRNA in a manner that improved its stability, thus increasing the abundance of FAK protein and enhancing the migration of these cells. High ADAR expression was a poor prognostic indicator in patients. These findings suggest that inhibiting FAK may be therapeutic in patients with ADAR-positive lung adenocarcinoma.

Abstract

Large-scale, genome-wide studies report that RNA binding proteins are altered in cancers, but it is unclear how these proteins control tumor progression. We found that the RNA-editing protein ADAR (adenosine deaminase acting on double-stranded RNA) acted as a facilitator of lung adenocarcinoma (LUAD) progression through its ability to stabilize transcripts encoding focal adhesion kinase (FAK). In samples from 802 stage I LUAD patients, increased abundance of ADAR at both the mRNA and protein level correlated with tumor recurrence. Knocking down ADAR in LUAD cells suppressed their mesenchymal properties, migration, and invasion in culture. Analysis of 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 ADAR posttranscriptionally 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.

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