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Updated: Jan 23, 2026

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
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Positive feedback regulation between USP8 and Hippo/YAP axis drives triple-negative breast cancer progression

Xin Li1,2, Penghe Yang1,3, Tianshi Wang4

  • 1Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan Province, PR China.

Cell Death & Disease
|January 21, 2026
PubMed

Insights

Ubiquitin Specific Peptidase 8 (USP8) stabilizes YAP, promoting triple-negative breast cancer (TNBC) progression. Inhibiting USP8 halts TNBC growth, suggesting USP8 as a potential therapeutic target for this aggressive cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The Hippo/Yao (YAP) signaling pathway is hyperactivated in triple-negative breast cancer (TNBC), driving tumor progression.
  • While the inhibitory phospho-cascade remains functional, the over-activation of YAP in TNBC is not fully understood.
  • Ubiquitin modifications of YAP are increasingly recognized for their role in cancer progression.

Purpose of the Study:

  • To investigate the mechanisms of ubiquitination and deubiquitination in YAP function within TNBC.
  • To identify critical deubiquitinating enzymes (DUBs) involved in YAP regulation in TNBC.
  • To explore the therapeutic potential of targeting DUBs in TNBC.

Main Methods:

  • Conducted siRNA screening using a deubiquitinase (DUB) library to identify key DUBs affecting YAP.
  • Performed biochemical assays to elucidate the interaction between USP8 and YAP.
  • Analyzed clinical data to correlate USP8 expression with patient survival and YAP protein levels in TNBC.

Main Results:

  • Identified Ubiquitin Specific Peptidase 8 (USP8) as a crucial effector in YAP function and TNBC progression.
  • Demonstrated that USP8 inhibition significantly hampered TNBC progression by modulating Hippo signaling.
  • Found that USP8 directly binds to the YAP promoter, enhancing its transcription and establishing a positive feedback loop.

Conclusions:

  • USP8 enhances YAP stability by suppressing K48-linked polyubiquitination, contributing to TNBC progression.
  • A positive feedback loop exists between USP8 and Hippo signaling in TNBC.
  • USP8 represents a promising therapeutic target for treating triple-negative breast cancer.

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