2. Academic Validation
  3. Positive feedback regulation between USP8 and Hippo/YAP axis drives triple-negative breast cancer progression

Positive feedback regulation between USP8 and Hippo/YAP axis drives triple-negative breast cancer progression

  • Cell Death Dis. 2026 Jan 21;17(1):98. doi: 10.1038/s41419-025-08356-8.
Xin Li # 1 2,  Penghe Yang # 1 3,  Tianshi Wang # 4,  Peng Su # 5,  Chenmiao Zhang 1 3 6 7,  Shen Fangyu 1 3 6 7,  Huijie Yang 1 3 6 7,  Jian Zhu 8,  Xiaodong Tan 9,  Ting Zhuang 10 11 12 13
Affiliations

Affiliations

  • 1 Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan Province, PR China.
  • 2 Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, PR China.
  • 3 Henan Key Laboratory of Immunology and Targeted Therapy, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan Province, PR China.
  • 4 Department of General Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, PR China.
  • 5 Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, PR China.
  • 6 Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan Province, PR China.
  • 7 Henan International Joint Laboratory of Immunology and Model Animals, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan Province, PR China.
  • 8 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, PR China. [email protected].
  • 9 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, PR China. [email protected].
  • 10 Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan Province, PR China. [email protected].
  • 11 Henan Key Laboratory of Immunology and Targeted Therapy, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan Province, PR China. [email protected].
  • 12 Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan Province, PR China. [email protected].
  • 13 Henan International Joint Laboratory of Immunology and Model Animals, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan Province, PR China. [email protected].
  • # Contributed equally.
PMID: 41565619 DOI: 10.1038/s41419-025-08356-8
Abstract

The hyper-activation of the Hippo/YAP axis was observed in triple-negative breast Cancer (TNBC), which was crucial for tumor progression. The over-activation of YAP in TNBC remains unexplained, despite the continued functionality of the inhibitory phospho-cascade. Recently, studies revealed that the ubiquitin modifications of YAP also play important roles in the Hippo/YAP axis and Cancer progression. In order to understand the potential mechanisms of ubiquitination and deubiquitination process in YAP function, we carried out siRNA screening for critical deubiquitinases in TNBC. Via the deubiquitinases (DUB) library, we identified Ubiquitin Specific Peptidase 8 (USP8) as an important effector in YAP function and TNBC progression. Inhibition of USP8 hampered TNBC progression via Hippo signaling. Clinical data revealed that USP8 expression correlated with YAP protein level and poor survival in TNBC patients. Biochemical evaluations revealed that USP8 has the ability to connect with YAP and suppress K48-linked polyubiquitination, thereby enhancing the stability of YAP. Interestingly, YAP directly binds to the USP8 promoter region, enhancing its transcription in TNBC. Our study revealed a forward feedback loop between USP8 and Hippo signaling in TNBC, indicating USP8 as a potential therapeutic drug targets in TNBC.

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