Dishevelled proteins and CYLD reciprocally regulate each other in CML cell lines

Abstract

Dishevelled (Dvl) proteins are activated by Wnt pathway stimulation and have crucial roles in the regulation of β-catenin destruction complex. CYLD is a tumor suppressor and a deubiquitination enzyme. CYLD negatively regulates the Wnt/β-catenin signaling pathway by deubiquitinating Dvl proteins. Loss of function and mutations of CYLD were linked to different types of solid tumors. Loss of function in CYLD is associated with Dvl hyper ubiquitination, resulting in the transmission of Wnt signaling to downstream effectors. β-catenin upregulation is observed during disease progression in chronic myeloid leukemia (CML). Deregulated Dvl signaling may be a reason for β-catenin activation in CML; and CYLD may contribute to Dvl deregulation. First, we evaluated mRNA expression in three CML cell lines and mRNA expression of the CYLD gene was found to be present in all (K562, MEG01, KU812). Unlike solid tumors sequencing revealed no mutations in the coding sequences of the CYLD gene. DVL genes were silenced by using a pool of siRNA oligonucleotides and gene expression differences in CYLD was determined by RT-PCR and western blot. CYLD protein expression decreased after Dvl silencing. An opposite approach of overexpressing Dvl proteins resulted in upregulated CYLD expression. While previous reports have described CYLD as a regulator of DVL proteins; our data suggests the presence of a more complicated reciprocal regulatory mechanism in CML cell lines.

Associations of A20, CYLD, Cezanne and JAK2 Genes and Immunophenotype with Psoriasis Susceptibility

“…In agreement, A20 prevents inflammatory reactions in psoriatic arthritis-like disease [29], and the inactivation of A20 is related to psoriasis severity [18]. Unlike A20, the inactivation of CYLD is found in blood cancers, including leukemia [13], and a downregulated expression of Cezanne is reported in solid cancers, such as hepatocellular carcinoma [16].…”

“…Among them, deubiquitinase (DUB) genes, including tumor necrosis factor α-induced protein 3 (TNFAIP3, A20), tumor suppressor cylindromatosis (CYLD) and Cezanne, play important roles in deubiquitinating target proteins by cleaving their polyubiquitin chains to suppress the activation of downstream signalling pathways. The attenuated expression of A20 and CYLD is shown in patients with leukemia/lymphoma [13][14][15] and Cezanne is down-regulated in hepatocellular carcinoma [16]. A20 variants are associated with susceptibility to psoriasis in a Japanese population [17].…”

MiR-182-5p Is Upregulated in Hepatic Tissues from a Diet-Induced NAFLD/NASH/HCC C57BL/6J Mouse Model and Modulates Cyld and Foxo1 Expression

“…Cyld negatively regulates NF-kB, known to be one of the most important players in inflammation and liver cancer [57], and the MAPK signaling cascade [58,59] by removing ubiquitin chains from signaling molecules, such as NEMO, TRAF2, TRAF6, TRAF7, TAK1 and RIP1 [60]. Moreover, Cyld induces the decrease in Wnt/β-catenin signaling activity by disheveled deubiquitination [61] and is considered an important regulator of necroptosis [62]. Furthermore, Nikolau et al [63] demonstrated that Cyld is involved in the regulation of hepatocyte homeostasis and that its inactivation causes inflammation, fibrosis and cancer through chronic activation of the TGF-beta-activated kinase (TAK1) and c-Jun N-terminal kinase (JNK).…”

Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential

“…Some of these substrates act as CSCs factors, which can activate and upregulate the SRSs. For example, the upregulation of CYLD causes DVL deubiquitination, significantly inhibiting the oncogenic Wnt pathway, thereby inhibiting the occurrence of tumors ( Caliskan et al, 2017 ). The downregulation of CYLD promotes the accumulation of β-catenin in the nucleus through ubiquitination of DVL at Lys-63 ( Tauriello et al, 2010 ).…”