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Updated: Jan 16, 2026

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
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Published on: July 25, 2019

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USP9X is a mechanosensitive deubiquitinase that controls tumor cell invasiveness and drug response through YAP

Pierric Biber1, Alexandrine Carminati1, Walaa Mohager1

  • 1Université Côte d'Azur, INSERM, C3M, 06204 Nice, France; Team Microenvironment, Signaling and Cancer, Equipe labellisée Ligue contre la Cancer, Nice, France.

Cell Reports
|October 2, 2025
PubMed

Insights

Deubiquitinases (DUBs) like USP9X sense extracellular matrix stiffness, controlling cancer cell YAP levels. Targeting USP9X inhibits cancer progression and enhances BRAF therapies by blocking mechanosensing.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Deubiquitinases (DUBs) are vital for protein homeostasis, but their role in sensing mechanical cues from the extracellular matrix (ECM) is unknown.
  • Tumor cells adapt to stress, yet the mechanisms linking DUBs to mechanical signal transduction remain unexplored.

Purpose of the Study:

  • To investigate the role of DUBs in sensing ECM mechanical properties in melanoma.
  • To identify specific DUBs involved in mechanotransduction and their downstream targets.

Main Methods:

  • Melanoma cells were cultured on collagen matrices with varying stiffness.
  • Activity-based protein profiling and quantitative proteomics were employed to identify stiffness-sensitive DUBs.
  • Western blotting and immunofluorescence were used to assess protein levels and localization.

Main Results:

  • Ubiquitin-specific peptidase 9 X-linked (USP9X) was identified as a stiffness-sensitive DUB.
  • USP9X regulates the mechanosensor YAP by deubiquitination, preventing its proteasomal degradation.
  • USP9X inhibition reduced YAP levels, impaired melanoma cell migration, invasion, ECM contraction, and decreased metastatic potential in vivo.

Conclusions:

  • USP9X acts as a mechanoresponsive DUB, crucial for cancer cell adaptation to ECM stiffness via the DDR/actomyosin pathway.
  • Targeting USP9X inhibits YAP-mediated mechanosensing, potentially overcoming drug resistance and reducing tumor relapse.
  • USP9X represents a novel, targetable therapeutic strategy in cancer treatment, particularly in combination with BRAF-targeted therapies.
Keywords:
CP: CancerCP: Cell biologyDUBUSP9XYAPextracellular matrix stiffnessinvasionmechanotransductiontherapy resistanceubiquitin proteasome system

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