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

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

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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