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

  • Cell Death Discov. 2025 Dec 30. doi: 10.1038/s41420-025-02925-8.
Qin Feng  #  1 ,  Qianfang Hu  #  2 ,  Qinghe Huang  #  1 ,  Jingxing Yang  3 ,  Ying Zhu  2 ,  Feng Wang  2 ,  Jianyu Xu  2 ,  Sha Hu  1 ,  Rujuan Zheng  1 ,  Hui Shi  1 ,  Zengyan Zhu  4 ,  Xinyuan Ding  5 ,  Wenjuan Wang  6
Affiliations
  • 1. Department of Pharmacy, Children's Hospital of Soochow University, Suzhou, China.
  • 2. Department of Pharmacy, Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China.
  • 3. National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China.
  • 4. Department of Pharmacy, Children's Hospital of Soochow University, Suzhou, China. [email protected].
  • 5. Department of Pharmacy, Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China. [email protected].
  • 6. Department of Pharmacy, Children's Hospital of Soochow University, Suzhou, China. [email protected].
  • # Contributed equally.
PMID: 41469388 DOI: 10.1038/s41420-025-02925-8
Abstract

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.

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