WWC3 regulates the Wnt and Hippo pathways via Dishevelled proteins and large tumour suppressor 1, to suppress lung cancer invasion and metastasis

Abstract

The scaffolding protein WWC (WW and C2-domain containing) family is known to regulate cell proliferation and organ size via the Hippo signalling pathway. However, the expression level of WWC3 in human tumours and the mechanisms underlying its role in cellular signal transduction have not yet been reported. Herein, we explored the potential roles of WWC3 in lung cancer cells and the corresponding molecular mechanisms. We found low WWC3 expression in both lung cancer cell lines and lung cancer specimens, which was associated with low differentiation, advanced pTNM stage, positive lymph node metastasis, and poor prognosis in patients with lung cancer. Moreover, the overexpression of WWC3 inhibited the proliferation and invasiveness of lung cancer cells. These effects were mediated by the inhibition and stimulation of the Wnt and Hippo pathways, respectively, in vitro and in vivo. Specifically, WWC3 interacts with Dishevelled (Dvl) proteins, prevents casein kinase 1 from phosphorylating Dvls, and inhibits -catenin nuclear translocation to inhibit the Wnt pathway. Deleting the WW and C-terminal PDZ-binding domains of WWC3 abrogated these effects. Moreover, the interaction of WWC3 with Dvls reduced the interaction between WWC3 and large tumour suppressor 1 (LATS1), as well as decreasing LATS1 phosphorylation to increase the nuclear importation of yes-associated protein (YAP) and attenuate the Hippo pathway. Deleting the WW domain of WWC3 abrogated this effect. These findings demonstrate the molecular interplay between WWC3, Dvls, and LATS1, and reveal a link between the Wnt and Hippo pathways, which provides a potential target for clinical intervention in lung cancer.

Long non‐coding RNA LINC00968 acts as oncogene in NSCLC by activating the Wnt signaling pathway

“…Wnt/β‐catenin signaling pathway has been reported to play a crucial role in multiple aspects of tumor progression, including NSCLC (Han et al, ; Seto et al, ; Tang et al, ). In addition, it has been known that Wnt/β‐catenin signaling pathway is involved in cancer invasion and metastasis (Farahmand, Darvishi, Majidzadeh‐A, & Ansari, ; Rong, Zhao, & Lu, ).…”

RASSF10 suppresses lung cancer proliferation and invasion by decreasing the level of phosphorylated LRP6

“…Wnt‐Hippo crosstalk has been well established among tumor cells . These two pathways are closely related to apoptosis, proliferation, invasion, and metastasis.…”

Reaping Wnt after calming Hippo: Wnt and Hippo signaling cross paths in lung cancer

“…Beyond this "cell density" aspect both pathways may also coordinate in managing the immune phenotype and apoptosis of cancer cells (10,11). Han et al (2) have expanded our knowledge and have shown that an upstream component of Hippo signaling, WWC3, not only inhibits YAP1, it also inhibits beta-catenin accumulation in the nucleus.…”

“…However, this causes WWC3 or WWC family members to become weak spots in the anti-tumor defense system. Han et al showed that WWC3 expression is down-regulated during lung cancer progression and its expression may become a novel marker for poor prognosis of non-small cell lung cancer (2). WWCs are highly similar and they all have the ability to regulate LATS1/2 protein function.…”

“…Before systems biology can truly thrive, sometimes simple steps must be taken to determine the crosstalks between individual signaling pathways. A recent paper published by Han et al (2) in the Journal of Pathology illuminated just such a step. This piece of the puzzle will aid in our understanding of how complex organisms form during embryogenesis, how they are maintained in adult life, and how they are prevented from falling prey to the chaotic forces of cancer.…”