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