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Tuesday 25 June 11:30

UBTD1 is a mechano-regulator controlling cancer aggressiveness

Journal article
Authors S. Torrino
F. R. Roustan
L. Kaminski
T. Bertero
S. Pisano
D. Ambrosetti
M. Dufies
Jay Uhler
E. Lemichez
A. Mettouchi
M. Gesson
K. Laurent
C. Gaggioli
J. F. Michiels
C. Lamaze
F. Bost
S. Clavel
Published in Embo Reports
Volume 20
Issue 4
ISSN 1469-221X
Publication year 2019
Published at Institute of Biomedicine
Language en
Links dx.doi.org/10.15252/embr.201846570
Keywords matrix stiffness, ROCK2, UBTD1, YAP, beta-TrCP, cell-cell adhesion, hippo pathway, size-control, yap/taz, yap, growth, stiffness, proteins
Subject categories Cancer and Oncology, Cell and Molecular Biology

Abstract

Ubiquitin domain-containing protein 1 (UBTD1) is highly evolutionary conserved and has been described to interact with E2 enzymes of the ubiquitin-proteasome system. However, its biological role and the functional significance of this interaction remain largely unknown. Here, we demonstrate that depletion of UBTD1 drastically affects the mechanical properties of epithelial cancer cells via RhoA activation and strongly promotes their aggressiveness. On a stiff matrix, UBTD1 expression is regulated by cell-cell contacts, and the protein is associated with beta-catenin at cell junctions. Yes-associated protein (YAP) is a major cell mechano-transducer, and we show that UBTD1 is associated with components of the YAP degradation complex. Interestingly, UBTD1 promotes the interaction of YAP with its E3 ubiquitin ligase beta-TrCP. Consequently, in cancer cells, UBTD1 depletion decreases YAP ubiquitylation and triggers robust ROCK2-dependent YAP activation and downstream signaling. Data from lung and prostate cancer patients further corroborate the in cellulo results, confirming that low levels of UBTD1 are associated with poor patient survival, suggesting that biological functions of UBTD1 could be beneficial in limiting cancer progression.

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