A positive feedback loop between TNS1 and ZEB1 promotes TGFβ-induced epithelial-to-mesenchymal transition in lung cancer

Epithelial-mesenchymal transition (EMT) plays a pivotal role in tumor metastasis initiation. Although emerging evidence suggests that Tensin-1 (TNS1) contributes to tumor metastasis, its precise function in EMT during lung cancer progression and the underlying mechanisms remain unclear. Here, we identify that TNS1 is upregulated in a TGFβ-induced EMT cell model. Functional studies demonstrate that TNS1 knockdown significantly attenuates both TGFβ- and hypoxia-induced EMT, highlighting its critical role in this process. Furthermore, TNS1 overexpression promotes EMT and enhances the metastatic potential of lung cancer cells in vitro and in vivo, while knockdown of TNS1 exhibits opposite effects. Mechanistically, TNS1 upregulation during TGFβ- mediated EMT is found to be transcriptionally regulated by ZEB1 and SMAD3. Notably, elevated TNS1 levels stabilizes ZEB1 through their interaction, thereby suppressing its ubiquitin-proteasomal degradation. Collectively, these findings uncover a positive feedback loop between TNS1 and ZEB1 that amplifies TGFβ-induced EMT and promotes lung cancer metastasis. TNS1, a focal adhesion protein that is upregulated during TGFβ -induced EMT, promotes metastasis of lung cancer via forming a positive feed-back loop with ZEB1, leading to ZEB1 upregulation by preventing its ubiquitin-proteasomal degradation.