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

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

Induction of Apoptosis by Rewiring the Signal Transduction of Epstein-Barr Virus Oncoprotein LMP1 toward Caspase Activation

The Epstein-Barr virus latent membrane protein 1 (LMP1) is an oncoprotein which mimics activated tumor necrosis factor receptor family members. Here we demonstrate the principle that an inducible association of the LMP1 cytoplasmic carboxyl terminus with caspase-8 by a heterodimerizing agent causes apoptosis. This process depends on the catalytic activity of caspase-8 and the ability of LMP1 to oligomerize constitutively at the plasma membrane. Our data indicate that chemical inducers of the association of the LMP1 carboxyl terminus with caspase-8 can kill LMP1-expressing cells selectively. Such compounds could be used as chemotherapeutic agents for LMP1-associated malignancies

Characterization of tumor suppressor CYLD expression in clear cell renal cell carcinoma

Cyld is a tumor suppressor gene that has attracted particular interest recently, due to its involvement in many types of neo-plasia, including head and neck squamous cell carcinoma, multiple myeloma, melanoma, hepatocellular carcinoma and colon cancer. Cyld encodes a predominantly cytoplasmic protein (CYLD), which is a deubiquitinating enzyme that regulates primarily cell survival and cell division pathways. Studies on the molecular function of CYLD have shown that it can modulate NF-κΒ, JNK, p38, TGF-beta, Wnt and Notch signaling. The present study aimed to investigate whether CYLD expression can be correlated with the development of clear cell renal cell carcinoma (ccRCC). Towards this goal, immunohistochemistry and Real Time PCR experiments were performed in order to analyze CYLD expression in clear cell renal cell carcinoma and matched normal tissue specimens. In addition, a clonogenic assay was performed to analyze the effect of CYLD wt and a catalytically inactive mutant CYLD on the growth of human embryonic kidney cells. The results of the present study show that CYLD is downregulated at protein and mRNA level in patients with ccRCC. This is further corroborated by the results of a clonogenic assay, which showed a deubiquitinating activity-dependent growth inhibitory role of CYLD in human embryonic kidney cells. Our results support the notion that CYLD can have a tumor suppressing role, at least in a subset of clear cell renal cell carcinoma, suggesting that it can be incorporated in the future in the development of targeted therapeutic approaches