UCHL1 stabilizes Twist1 via K11/K63-linked deubiquitination to drive tumor metastasis in non-small cell lung cancer.

Deubiquitinating enzymes (DUBs) are critical regulators of protein turnover and have emerged as key players in cancer progression. In this study, we demonstrated that ubiquitin C-terminal hydrolase L1 (UCHL1) is upregulated in non-small cell lung cancer (NSCLC) and drives tumor metastatic progression, and we identified Twist1, a transcription factor that governs epithelial-mesenchymal transition (EMT), as a downstream target of UCHL1. Depletion of UCHL1 attenuated Twist1-mediated metastatic capacity in NSCLC cells both in vitro and in vivo. Mechanistically, UCHL1 directly interacts with Twist1 and stabilizes Twist1 protein levels through the enzymatic cleavage of K11- and K63-linked ubiquitin chains. Clinically, immunohistochemistry of human NSCLC tissues revealed a positive correlation between UCHL1/Twist1 expression and metastatic progression, with elevated levels of both proteins predicting poor prognosis. Our findings reveal a critical pathway through which UCHL1-mediated deubiquitination sustains Twist1 stability, revealing a novel posttranslational regulatory axis involved in cancer metastasis and progression and highlighting promising therapeutic targets for metastatic NSCLC.