Fascin induces melanoma tumorigenesis and stemness through regulating the Hippo pathway

Jiaxin Kang,Jianwei Sun,Yan Sun,Feng Gao,Zhuang Yao,Yuanzhao Hu,Jian Wang,Qin Fan,Shijie Ma

doi:10.1186/s12964-018-0250-1

Abstract

BackgroundFascin is a F-actin bundling protein and its overexpression is correlated with poor prognosis and increases metastatic potential in a number of cancers. But underlying function and mechanism of fascin on tumorigenesis in melanoma remain elusive.MethodsThe melanoma cell lines WM793 and WM39 were employed for the soft agar and sphere formation assay. Quantitative RT-PCR and Western blot were performed for identifying the gene expression at mRNA and protein levels, respectively. Co-IP and in vitro GST pulldown experiments were used to test the interaction between fascin and MST2.ResultsFascin regulates tumorigenesis and cancer cell stemness in melanoma through inhibition of the Hippo pathway kinase MST2 and the activation of transcription factor TAZ. Our data showed that fascin interacts with the kinase domain of MST2 to inhibit its homodimer formation and kinase activity. Depletion of fascin led to increase of p-LATS level and decrease of TAZ, but not YAP. We also demonstrated that fascin regulates melanoma tumorigenesis independent of its actin-bundling activity.ConclusionsFascin is a new regulator of the MST2-LATS-TAZ pathway and plays a critical role in melanoma tumorigenesis. Inhibition of fascin reduces melanoma tumorigenesis and stemness, and thus fascin could be a potential therapeutic target for this malignancy.

Highlights

Fascin is a F-actin bundling protein and its overexpression is correlated with poor prognosis and increases metastatic potential in a number of cancers
Fascin is a new regulator of the MST2-LATS-Transcriptional co-activator with PDZ-binding motif (TAZ) pathway and plays a critical role in melanoma tumorigenesis
Our results showed that deletion of fascin in WM793 cells dramatically reduced anchorage-independent growth (Fig. 1b and c) and the number of melanoma sphere by more than 50% (Fig. 1d and e)

Summary

Introduction

Fascin is a F-actin bundling protein and its overexpression is correlated with poor prognosis and increases metastatic potential in a number of cancers. An actin-bundling protein, is a key element in tumor metastasis [1, 2] and has been shown to regulate assembly of actin bundles. Fascin bundles actin through three binding sites and generates protrusive force to drive cancer metastasis [3,4,5]. It is generally thought that the causal role of fascin in tumor metastasis predominantly depends on its actin-bundling activity. The core components of the Hippo pathway include serine/threonine kinase MST (Mammalian Sterile 20 Like kinase), LATS (large tumor suppressor kinase) and major downstream mediator YAP (Yes Associated Protein)/TAZ (Trascriptional Coactivator with PDZ-binding motif). Activation of two kinases, MST and LATS, leads to LATS-dependent phosphorylation of YAP/TAZ, limiting their stability, nuclear localization and transcriptional activity

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