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The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGF? Signaling

Pseftogas, A; Xanthopoulos, K; Poutahidis, T; Ainali, C; Dafou, D; Panteris, E; Kern, JG; Varelas, X; Hardas, A; Gonidas, C; Tsingotjidou, A; Hatzivassiliou, E; Mosialos, G


A Pseftogas

K Xanthopoulos

T Poutahidis

C Ainali

D Dafou

E Panteris

JG Kern

X Varelas

A Hardas

C Gonidas

A Tsingotjidou

E Hatzivassiliou

G Mosialos


Downregulation of the cylindromatosis (CYLD) tumor suppressor has been associated with breast cancer development and progression. Here, we report a critical role for CYLD in maintaining the phenotype of mammary epithelial cells in vitro and in vivo. CYLD downregulation or inactivation induced an epithelial to mesenchymal transition of mammary epithelial cells that was dependent on the concomitant activation of the transcription factors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and transforming growth factor beta (TGF?)signaling. CYLD inactivation enhanced the nuclear localization of YAP/TAZ and the phosphorylation of Small Mothers Against Decapentaplegic (SMAD)2/3 proteins in confluent cell culture conditions. Consistent with these findings were the hyperplastic alterations of CYLD-deficient mouse mammary epithelia, which were associated with enhanced nuclear expression of the YAP/TAZ transcription factors. Furthermore, in human breast cancer samples, downregulation of CYLD expression correlates with enhanced YAP/TAZ-regulated target gene expression. Our results identify CYLD as a critical regulator of a signaling node that prevents the coordinated activation of YAP/TAZ and the TGF? pathway in mammary epithelial cells, in order to maintain their phenotypic identity and homeostasis. Consequently, they provide a novel conceptual framework that supports and explains a causal implication of deficient CYLD expression in aggressive human breast cancers.


Pseftogas, A., Xanthopoulos, K., Poutahidis, T., Ainali, C., Dafou, D., Panteris, E., …Mosialos, G. (2020). The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling. Cancers, 12(8), 2047.

Journal Article Type Article
Acceptance Date Jul 13, 2020
Publication Date Jul 24, 2020
Deposit Date Aug 14, 2020
Publicly Available Date Nov 20, 2020
Journal Cancers
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 12
Issue 8
Pages 2047
Public URL
Publisher URL


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