Dataset Information

YAP-dependent ubiquitination and degradation of ?-catenin mediates inhibition of Wnt signalling induced by Physalin F in colorectal cancer.

ABSTRACT: 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.

SUBMITTER: Chen C

PROVIDER: S-EPMC5964149 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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YAP-dependent ubiquitination and degradation of β-catenin mediates inhibition of Wnt signalling induced by Physalin F in colorectal cancer.

Chen Chen C Zhu Dongrong D Zhang Hao H Han Chao C Xue Guimin G Zhu Tianyu T Luo Jianguang J Kong Lingyi L

Cell death & disease 20180522 6

Aberrant activation of Wnt/β-catenin signalling is critical in the progression of human cancers, especially colorectal cancer (CRC). Therefore, inhibition of Wnt/β-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/β-catenin signalling. In vitro, PF decreased Wnt3a-induced TOPFlash reporter activity in HEK293T cells and promoted the fo ...[more]

PMID: 29789528

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Project description:Aberrant regulation of the Wnt/β-catenin signaling pathway is one of the major causes of colorectal cancer (CRC). Loss-of-function mutations in APC are commonly found in CRC, leading to inappropriate activation of canonical Wnt signaling. Conversely, gain-of-function mutations in KRAS and BRAF genes are detected in up to 60% of CRCs. Whereas KRAS/mitogen-activated protein kinase (MAPK) and canonical Wnt/β-catenin pathways are critical for intestinal tumorigenesis, mechanisms integrating these two important signaling pathways during CRC development are unknown. Results herein demonstrate that transformation of normal intestinal epithelial cells (IECs) by oncogenic forms of KRAS, BRAF or MEK1 was associated with a marked increase in β-catenin/TCF4 and c-MYC promoter transcriptional activities and mRNA levels of c-Myc, Axin2 and Lef1. Notably, expression of a dominant-negative mutant of T-Cell Factor 4 (ΔNTCF4) severely attenuated IEC transformation induced by oncogenic MEK1 and markedly reduced their tumorigenic and metastatic potential in immunocompromised mice. Interestingly, the Frizzled co-receptor LRP6 was phosphorylated in a MEK-dependent manner in transformed IECs and in human CRC cell lines. Expression of LRP6 mutant in which serine/threonine residues in each particular ProlineProlineProlineSerine/ThreonineProline motif were mutated to alanines (LRP6-5A) significantly reduced β-catenin/TCF4 transcriptional activity. Accordingly, MEK inhibition in human CRC cells significantly diminished β-catenin/TCF4 transcriptional activity and c-MYC mRNA and protein levels without affecting β-catenin expression or stability. Lastly, LRP6 phosphorylation was also increased in human colorectal tumors, including adenomas, in comparison with healthy adjacent normal tissues. Our data indicate that oncogenic activation of KRAS/BRAF/MEK signaling stimulates the canonical Wnt/β-catenin pathway, which in turn promotes intestinal tumor growth and invasion. Moreover, LRP6 phosphorylation by ERK1/2 may provide a unique point of convergence between KRAS/MAPK and Wnt/β-catenin signalings during oncogenesis.

Dataset Information

YAP-dependent ubiquitination and degradation of ?-catenin mediates inhibition of Wnt signalling induced by Physalin F in colorectal cancer.

Publications

YAP-dependent ubiquitination and degradation of β-catenin mediates inhibition of Wnt signalling induced by Physalin F in colorectal cancer.

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