Fascin induces melanoma tumorigenesis and stemness through regulating the Hippo pathway

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.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0250-1) contains supplementary material, which is available to authorized users.

Mass spectrometry‐based proteomic analysis of FSCN1‐interacting proteins in laryngeal squamous cell carcinoma cells

“…Later, nesprin‐2 was found to bind to FSCN1 and play a key role in nuclear movement and deformation . Moreover, two serine/threonine kinases (mammalian STE20‐like 1/2; [MST1/2]) and an epithelial‐mesenchymal transition (EMT)‐promoting factor (Snail) were found physiologically interact with FSCN1, and the interaction serves to modulate cancer progression …”

How does fascin promote cancer metastasis?

“…There are reports indicating that fascin might have actin‐bundling independent functions in cancer [128]. Fascin has been shown to interact with a number of proteins other than F‐actin [24,123,129–131]. Although the functional implication of these interactions in cancer metastasis is largely unclear, we suspect that fascin might have much broader roles in cancer metastasis than promoting cancer cell migration and invasion.…”

“…In lung adenocarcinoma, inhibition of OXPHOS abrogates CSC self‐renewal by activation of AMP‐activated kinase and inhibition of Hippo pathway transcription factor YAP1 [113]. Intriguingly, fascin knockdown or knockout also inhibits CSC self‐renewal [22] and decreases YAP1 protein levels [24,123]. It remained to be determined whether fascin might control cancer cell stemness through enhancing mitochondrial metabolism.…”

“…It has been postulated that fascin has mechanical roles in promoting cancer cell migration and invasion during metastatic dissemination [5,12–16]. Intriguingly, there is also evidence implicating fascin in oncogenesis [17], metastatic colonization [18,19], anoikis resistance [17,20], chemoresistance [21], and cancer cell stemness [22–24]. In this state‐of‐the‐art review, we will summarize recent progress in fascin‐mediated cancer metastasis.…”

Immunohistochemical Fascin-1 expression correlate with lymph node and distant metastases in pancreatic ductal adenocarcinoma

“…There are many reports about role of Fascin-1 in the development and metastasis of many neoplasms such as melanoma, breast, lung and stomach cancer [14][15][16][17]. Several studies have shown that increase in expression of Fascin-1 correlates with tumours characterized by high metastatic potential and poor prognosis as well as shorter overall survival [12].…”