Quaking 5 suppresses TGF-β-induced EMT and cell invasion in lung adenocarcinoma.

Quaking (QKI) proteins belong to the signal transduction and activation of RNA (STAR) family of RNA-binding proteins that have multiple functions in RNA biology. Here, we show that QKI-5 is dramatically decreased in metastatic lung adenocarcinoma (LUAD). QKI-5 overexpression inhibits TGF-β-induced epithelial-mesenchymal transition (EMT) and invasion, whereas QKI-5 knockdown has the opposite effect. QKI-5 overexpression and silencing suppresses and promotes TGF-β-stimulated metastasis in vivo, respectively. QKI-5 inhibits TGF-β-induced EMT and invasion in a TGFβR1-dependent manner. KLF6 knockdown increases TGFβR1 expression and promotes TGF-β-induced EMT, which is partly abrogated by QKI-5 overexpression. Mechanistically, QKI-5 directly interacts with the TGFβR1 3' UTR and causes post-transcriptional degradation of TGFβR1 mRNA, thereby inhibiting TGF-β-induced SMAD3 phosphorylation and TGF-β/SMAD signaling. QKI-5 is positively regulated by KLF6 at the transcriptional level. In LUAD tissues, KLF6 is lowly expressed and positively correlated with QKI-5 expression, while TGFβR1 expression is up-regulated and inversely correlated with QKI-5 expression. We reveal a novel mechanism by which KLF6 transcriptionally regulates QKI-5 and suggest that targeting the KLF6/QKI-5/TGFβR1 axis is a promising targeting strategy for metastatic LUAD.