Quaking 5 suppresses TGF-?-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-?-induced epithelial-mesenchymal transition (EMT) and invasion, whereas QKI-5 knockdown has the opposite effect. QKI-5 overexpression and silencing suppresses and promotes TGF-?-stimulated metastasis in vivo, respectively. QKI-5 inhibits TGF-?-induced EMT and invasion in a TGF?R1-dependent manner. KLF6 knockdown increases TGF?R1 expression and promotes TGF-?-induced EMT, which is partly abrogated by QKI-5 overexpression. Mechanistically, QKI-5 directly interacts with the TGF?R1 3' UTR and causes post-transcriptional degradation of TGF?R1 mRNA, thereby inhibiting TGF-?-induced SMAD3 phosphorylation and TGF-?/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 TGF?R1 expression is upregulated 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/TGF?R1 axis is a promising targeting strategy for metastatic LUAD.

Quaking（QKI）蛋白属于RNA信号转导与激活（STAR）家族的RNA结合蛋白，在RNA生物学领域发挥多种功能。本研究证实，QKI-5在转移性肺腺癌（LUAD）中表达显著下调。过表达QKI-5可抑制转化生长因子-β（TGF-β）诱导的上皮间质转化（EMT）与细胞侵袭，而敲低QKI-5则会产生相反效应。体内实验表明，QKI-5过表达可抑制TGF-β诱导的肿瘤转移，敲低QKI-5则会促进该过程。QKI-5以依赖于转化生长因子β受体1（TGFβR1）的方式抑制TGF-β诱导的EMT与细胞侵袭。敲低KLF6可上调TGFβR1的表达并促进TGF-β诱导的EMT，而过表达QKI-5可部分逆转这一效应。机制研究显示，QKI-5可直接结合TGFβR1的3'非翻译区（3' UTR），并介导TGFβR1 mRNA的转录后降解，进而抑制TGF-β诱导的SMAD3磷酸化及TGF-β/SMAD信号通路。在转录水平上，QKI-5的表达受KLF6的正向调控。在肺腺癌（LUAD）组织中，KLF6呈低表达且与QKI-5的表达呈正相关，而TGFβR1的表达则呈上调趋势且与QKI-5的表达呈负相关。本研究揭示了KLF6转录调控QKI-5的全新机制，并提示靶向KLF6/QKI-5/TGFβR1信号轴有望成为治疗转移性肺腺癌（LUAD）的潜在策略。