Atorvastatin exhibits anticancer effects by inhibiting YAP/TAZ activity in mesenchymal-like non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for most lung cancer diagnoses. Statins preferentially inhibit the proliferation of mesenchymal- over epithelial-like cells in various types of cancer, including NSCLCs. However, the mechanisms underlying the differential statin sensitivity of mesenchymal and epithelial cancer cells remain unknown. Statins inhibit YAP/TAZ, effectors of the Hippo pathway, via depletion of geranylgeranyl pyrophosphate. Here, we aimed to elucidate the mechanisms underlying statin sensitivity in mesenchymal cancer. We explored the anticancer effects of atorvastatin and its association with YAP/TAZ activity in NSCLC cell lines with different epithelial-mesenchymal phenotypes. Atorvastatin significantly reduced the proliferation, migration, and invasion of mesenchymal-like cells, while showing negligible effect on epithelial-like cells. Atorvastatin also inhibited YAP/TAZ nuclear localization and downstream gene expression in mesenchymal cells but did not affect epithelial cells. Small interfering (si) RNA-mediated inhibition of both YAP and TAZ reduced the proliferation of all NSCLC cell lines tested, regardless of phenotype, indicating that sensitivity to YAP/TAZ inhibition and statins differ. In summary, our results suggest that inhibited YAP/TAZ nuclear localization by statins differs between epithelial and mesenchymal NSCLC cell lines, resulting in differential statin sensitivity.