YAP-dependent ubiquitination and degradation of ?-catenin mediates inhibition of Wnt signalling induced by Physalin F in colorectal cancer.
Aberrant activation of Wnt/?-catenin signalling is critical in the progression of human cancers, especially colorectal cancer (CRC). Therefore, inhibition of Wnt/?-catenin signalling is a significant potential target for CRC therapy. Here, we identified for the first time that Physalin F (PF), a steroid derivative isolated from Physalis angulate, acts as ... an antagonist of Wnt/?-catenin signalling. In vitro, PF decreased Wnt3a-induced TOPFlash reporter activity in HEK293T cells and promoted the formation of the ?-catenin destruction complex. Importantly, PF also inhibited Wnt/?-catenin signalling and accelerated the degradation of ?-catenin in CRC cells. However, PF did not affect the stabilization of Axin or the interaction of ?-catenin with E-cadherin. Interestingly, we further found that PF promoted YAP binding to the ?-catenin destruction complex, which facilitated the ubiquitination and degradation of ?-catenin. Silencing and pharmacological inhibition of YAP reversed the formation of the ?-catenin destruction complex induced by PF, implying that YAP binding to the ?-catenin destruction complex was responsible for PF-mediated inhibition of Wnt/?-catenin signalling. Furthermore, PF observably inhibited tumour growth by down-regulating ?-catenin in tumour-bearing mice. Collectively, our findings indicated that PF inhibited Wnt/?-catenin signalling by accelerating the ubiquitination and degradation of ?-catenin in a YAP-dependent manner and therefore PF could be a novel potential candidate for CRC therapy.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms, HEK293 Cells, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Phosphoproteins, Proteasome Endopeptidase Complex, Protein Stability, Proteolysis, Secosteroids, Transcription Factors, Ubiquitination, Wnt Signaling Pathway, Xenograft Model Antitumor Assays, beta Catenin, beta-Transducin Repeat-Containing Proteins
Adaptor Proteins, Signal Transducing, Animals, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms, HEK293 Cells, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Phosphoproteins, Proteasome Endopeptidase Complex, Protein Stability, Proteolysis, Secosteroids, Transcription Factors, Ubiquitination, Wnt Signaling Pathway, Xenograft Model Antitumor Assays, beta Catenin, beta-Transducin Repeat-Containing Proteins
Cell Death Dis
Date: Dec. 22, 2017
PubMed ID: 29789528
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