Abstract
Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. TRAP1 relevance in the activation of Wnt/β-Catenin signaling was highlighted by a TCF/LEF Cignal Reporter Assay in Wnt-off HEK293T and CRC HCT116 cell lines. Of note, this regulation occurs through the modulation of Wnt ligand receptors LRP5 and LRP6 that are both downregulated in TRAP1-silenced cell lines. However, while LRP5 mRNA is significantly downregulated upon TRAP1 silencing, LRP6 mRNA is unchanged, suggesting independent mechanisms of regulation by TRAP1. Indeed, LRP5 is regulated upon promoter methylation in CRC cell lines and human CRCs, whereas LRP6 is controlled at post-translational level by protein ubiquitination/degradation. Consistently, human CRCs with high TRAP1 expression are characterized by the co-upregulation of active β-Catenin, LRP5 and LRP6. Altogether, these data suggest that Wnt/β-Catenin signaling is modulated at multiple levels by TRAP1.
Highlights
Wnt pathway is an evolutionarily conserved signaling broadly involved in regulating embryonic development, regeneration, and cellular differentiation [1]
Upon Wnt interaction with receptors, the intracellular signal is transduced with the recruitment of cytoplasmic Disheveled phosphoproteins (Dvl) to membranes and this provides a site for Axis Inhibitor (AXIN) and Glycogen Synthase Kinase-3 (GSK3β) to bind and phosphorylate Lipoprotein-related proteins 5/6 (LRP5/6), preventing the constitutive degradation of β-Catenin [5]
Intracellular Wnt/β-Catenin signaling depends on the amount of the transcriptional co-activator β-Catenin, which migrates from the cytoplasm to the nucleus to engage the T cell Transcription Factor (TCF) or the Lymphoid Enhancer Factor (LEF) regulating the expression of several target genes involved in key cellular processes, such as c-Myc, cyclin D1, and CD44 [6,7]
Summary
Wnt pathway is an evolutionarily conserved signaling broadly involved in regulating embryonic development, regeneration, and cellular differentiation [1]. Upon Wnt interaction with receptors, the intracellular signal is transduced with the recruitment of cytoplasmic Disheveled phosphoproteins (Dvl) to membranes and this provides a site for Axis Inhibitor (AXIN) and Glycogen Synthase Kinase-3 (GSK3β) to bind and phosphorylate LRP5/6, preventing the constitutive degradation of β-Catenin [5]. Intracellular Wnt/β-Catenin signaling depends on the amount of the transcriptional co-activator β-Catenin, which migrates from the cytoplasm to the nucleus to engage the T cell Transcription Factor (TCF) or the Lymphoid Enhancer Factor (LEF) regulating the expression of several target genes involved in key cellular processes, such as c-Myc, cyclin D1, and CD44 [6,7]. In the absence of Wnt ligands, β-Catenin is degraded through phosphorylation and ubiquitination by a multimeric protein complex, known as destruction complex, consisting of several proteins, as Adenomatous Polyposis Coli (APC), AXIN, Casein Kinase 1 (CK1), and GSK3β [8]
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