2. Academic Validation
  3. USP21-mediated G3BP1 stabilization accelerates proliferation and metastasis of esophageal squamous cell carcinoma via activating Wnt/β-Catenin signaling

USP21-mediated G3BP1 stabilization accelerates proliferation and metastasis of esophageal squamous cell carcinoma via activating Wnt/β-Catenin signaling

  • Oncogenesis. 2024 Jun 21;13(1):23. doi: 10.1038/s41389-024-00524-3.
Jiazhong Guo # 1,  Yunpeng Zhao # 2,  Huacong Sui 2,  Lei Liu 2,  Fanrong Liu 2,  Lingxiao Yang 2,  Fengyuan Gao 2,  Jinfu Wang 2,  Yilin Zhu 2,  Lingbing Li 2,  Xiangqing Song 2,  Peng Li 2,  Zhongxian Tian 2 3,  Peichao Li 4 5,  Xiaogang Zhao 6 7
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 2 Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 3 Key Laboratory of Chest Cancer, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 4 Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. lipeichao@email.sdu.edu.cn.
  • 5 Key Laboratory of Chest Cancer, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. lipeichao@email.sdu.edu.cn.
  • 6 Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. zhaoxiaogang@sdu.edu.cn.
  • 7 Key Laboratory of Chest Cancer, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. zhaoxiaogang@sdu.edu.cn.
  • # Contributed equally.
PMID: 38906857 DOI: 10.1038/s41389-024-00524-3
Abstract

Lacking effective therapeutic targets heavily restricts the improvement of clinical prognosis for patients diagnosed with esophageal squamous cell carcinoma (ESCC). Ubiquitin Specific Peptidase 21 (USP21) is dysregulated in plenty of human cancers, however, its potential function and relevant molecular mechanisms in ESCC malignant progression as well as its value in clinical translation remain largely unknown. Here, in vitro and in vivo experiments revealed that aberrant upregulation of USP21 accelerated the proliferation and metastasis of ESCC in a deubiquitinase-dependent manner. Mechanistically, we found that USP21 binds to, deubiquitinates, and stabilizes the G3BP Stress Granule Assembly Factor 1 (G3BP1) protein, which is required for USP21-mediated ESCC progression. Further molecular studies demonstrated that the USP21/G3BP1 axis played a tumor-promoting role in ESCC progression by activating the Wnt/β-catenin signaling pathway. Additionally, disulfiram (DSF), an inhibitor against USP21 deubiquitylation activity, markedly abolished the USP21-mediated stability of G3BP1 protein and significantly displayed an anti-tumor effect on USP21-driving ESCC progression. Finally, the regulatory axis of USP21/G3BP1 was demonstrated to be aberrantly activated in ESCC tumor tissues and closely associated with advanced clinical stages and unfavorable prognoses, which provides a promising therapeutic strategy targeting USP21/G3BP1 axis for ESCC patients.

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