UBTD1 is a mechano‐regulator controlling cancer aggressiveness. (25th February 2019)

• Record Type: Journal Article
• Authors: Torrino, Stéphanie; Roustan, François‐René; Kaminski, Lisa; Bertero, Thomas; Pisano, Sabrina; Ambrosetti, Damien; Dufies, Maeva; Uhler, Jay P; Lemichez, Emmanuel; Mettouchi, Amel; Gesson, Maeva; Laurent, Kathiane; Gaggioli, Cedric; Michiels, Jean‐Francois; Lamaze, Christophe; Bost, Frédéric; Clavel, Stéphan
• Is Part Of: EMBO reports. Volume 20:Number 4(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-02-25
• Subjects: matrix stiffness -- ROCK2 -- UBTD1 -- YAP -- β‐TrCP; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201846570
• Languages: English
• ISSNs: 1469-221X

Abstract

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 β‐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 β‐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. Synopsis: In lung and prostate cancer, low levels of UBTD1 are associated with poor survival, suggesting that it limits cancer progression. UBTD1 depletion affects the mechanical properties of cancer cells, decreases YAP ubiquitylation and promotes YAP activation. UBTD1 regulates the mechanical properties of cancer cells via RhoA. UBTD1 depletion decreases YAP ubiquitylation and triggers robust ROCK2 dependent YAP signaling. UBTD1 represses cancer cell aggressiveness and its increased expression enhances patient survival. Abstract : In lung and prostate cancer, low levels of UBTD1 are associated with poor survival, suggesting that it limits cancer progression. UBTD1 depletion affects the mechanical properties of cancer cells, decreases YAP ubiquitylation and promotes YAP activation.