Abstract
WW domain binding protein-2 (WBP2) can function as a Yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) co-activator and has a crucial role in promoting breast cancer progression. However, the expression and potential molecular mechanisms of WBP2 in the context of lung cancer are not fully understood. We determined that WBP2 was highly expressed in lung cancer specimens and cell lines and that this expression was closely related to the advanced pTNM stage, lymph node metastasis, and poor prognosis of patients. In addition, gain- and loss-of-function experiments revealed that WBP2 could significantly promote the proliferation and invasion of lung cancer cells both in vivo and in vitro. To elucidate the underlying molecular mechanism, we determined that wild-type WBP2 could competitively bind to the WW domain of WWC3 (WW and C2 domain-containing-3) with LATS1 (Large tumor suppressor-1) through its PPxY motifs, thus inhibiting the formation of the WWC3-LATS1 complex, reducing the phosphorylation level of LATS1, suppressing the activity of the Hippo pathway, and ultimately promoting YAP nuclear translocation. Therefore, from the aspect of upstream molecules of Hippo signaling, WBP2 promotes the malignant phenotype of lung cancer cells in a unique manner that is not directly dependent upon YAP, thus providing a corresponding experimental basis for the development of targeted therapeutic drugs for lung cancer.
Highlights
The Hippo pathway, initially identified in Drosophila, is highly conserved across the evolution of species, playing a crucial role in maintaining homeostasis, regulating cell proliferation, differentiation, and other physiological processes
WW domain binding protein-2 (WBP2) is highly expressed in non-small cell lung cancer (NSCLC) and is associated with poor prognosis
To determine whether WBP2 has a specific role in NSCLC, we first detected the expression of WBP2 in lung cancer specimens, and further assessed the association of this expression with the survival and prognosis of patients via immunohistochemistry and immunofluorescence staining
Summary
The Hippo pathway, initially identified in Drosophila, is highly conserved across the evolution of species, playing a crucial role in maintaining homeostasis, regulating cell proliferation, differentiation, and other physiological processes. On activation of the classical Hippo pathway, the upstream molecules induce the phosphorylation of the central kinase MST-LATS (mammalian sterile 20-like kinase/large tumor suppressor) complex, promoting the phosphorylation of YAP. This protein remains in the cytoplasm, binds to the 14-3-3 protein, and is degraded by the ubiquitin-proteasome. Several studies have focused on the molecular function of WBP2 in human solid tumors by assessing the impact of this protein on the biological phenotype[10,11,12,13,14,15] Both the expression pattern of WBP2 in lung cancer and the ability of this protein to regulate the activity of the Hippo pathway in an indirect manner that is dependent upon YAP remain unreported
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