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

作者：Shengjie Wang, Xin Tong, Chang Li, Ersuo Jin, Zhiyue Su, Zelong Sun, Weiwei Zhang, Zhe Lei, Hongtao Zhang · 发表于：EMBO Reports · 年份：2021 · DOI：10.15252/embr.202052079 · 被引用次数：54 · 研究领域：Kruppel-like factors research、Cancer-related molecular mechanisms research、RNA Research and Splicing

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. The zinc finger transcription factor KLF6 and the RNA-binding protein Quaking 5 are dramatically reduced in metastatic lung adenocarcinoma. KLF6 tran...