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.