USP9X is a mechanosensitive deubiquitinase that controls tumor cell invasiveness and drug response through YAP stabilization
Abstract
Ubiquitin removal by deubiquitinases (DUBs) is crucial for protein activity and homeostasis. While tumor cells adapt to treatment and environmental stress, the role of DUBs in sensing mechanical signals from the extracellular matrix (ECM) remains an unexplored area. Using melanoma cells cultured on collagen matrices of varying stiffness and activity-based ubiquitin probe profiling combined with quantitative proteomics, we identify ubiquitin specific peptidase 9 X-linked (USP9X) as a stiffness-sensitive DUB acting through the discoidin domain receptor (DDR)/actomyosin signaling pathway. USP9X regulates levels of the mechanosensor YAP by preventing its proteasomal degradation via deubiquitination. Inhibition or knockdown of USP9X reduced YAP expression, impaired tumor cell migration, invasion, and ECM contraction, and decreased metastatic potential in vivo. Targeting USP9X also enhanced the effectiveness of BRAF-targeted therapies by limiting YAP-mediated mechanosensing, drug resistance, and tumor relapse. These findings establish USP9X as a mechanoresponsive DUB essential for cancer cell adaptation to mechanical cues, proposing it as a targetable mechanosensitive therapeutic target in cancer.
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BibTeX
@article{biber2026usp9x,
title = {{USP9X is a mechanosensitive deubiquitinase that controls tumor cell invasiveness and drug response through YAP stabilization}},
author = {Pierric Biber and Alexandrine Carminati and Walaa Mohager and Mickael Ohanna and Christophe Girard and Margaux Lecacheur and Mira Kahil and Océane Bouvet and Marie Irondelle and Stéphane Audebert and Mehdi Khaled and Sophie Tartare-Deckert and Marcel Deckert},
journal = {Cell Reports},
year = {2026},
month = oct,
doi = {10.1016/j.celrep.2025.116372},
url = {https://hal.science/hal-05775458v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - USP9X is a mechanosensitive deubiquitinase that controls tumor cell invasiveness and drug response through YAP stabilization
AU - Pierric Biber
AU - Alexandrine Carminati
AU - Walaa Mohager
AU - Mickael Ohanna
AU - Christophe Girard
AU - Margaux Lecacheur
AU - Mira Kahil
AU - Océane Bouvet
AU - Marie Irondelle
AU - Stéphane Audebert
AU - Mehdi Khaled
AU - Sophie Tartare-Deckert
AU - Marcel Deckert
PY - 2026
DA - 2026/10/02
JO - Cell Reports
DO - 10.1016/j.celrep.2025.116372
UR - https://hal.science/hal-05775458v1
AB - Ubiquitin removal by deubiquitinases (DUBs) is crucial for protein activity and homeostasis. While tumor cells adapt to treatment and environmental stress, the role of DUBs in sensing mechanical signals from the extracellular matrix (ECM) remains an unexplored area. Using melanoma cells cultured on collagen matrices of varying stiffness and activity-based ubiquitin probe profiling combined with quantitative proteomics, we identify ubiquitin specific peptidase 9 X-linked (USP9X) as a stiffness-sensitive DUB acting through the discoidin domain receptor (DDR)/actomyosin signaling pathway. USP9X regulates levels of the mechanosensor YAP by preventing its proteasomal degradation via deubiquitination. Inhibition or knockdown of USP9X reduced YAP expression, impaired tumor cell migration, invasion, and ECM contraction, and decreased metastatic potential in vivo. Targeting USP9X also enhanced the effectiveness of BRAF-targeted therapies by limiting YAP-mediated mechanosensing, drug resistance, and tumor relapse. These findings establish USP9X as a mechanoresponsive DUB essential for cancer cell adaptation to mechanical cues, proposing it as a targetable mechanosensitive therapeutic target in cancer.
SN - 2211-1247
SN - 2211-1247
ER -