Actin-bundling Protein Fascin Research Articles

Identification of novel molecules and pathways associated with fascin actin‑bundling protein 1 in laryngeal squamous cell carcinoma through comprehensive transcriptome analysis.

Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor with a poor prognosis. Fascin actin‑bundling protein 1 (FSCN1) has been reported to play a crucial role in the development and progression of LSCC; however, the underlying molecular mechanisms remain unknown. Herein, a whole transcriptome microarray analysis was performed to screen for differentially expressed genes (DEGs) in cells in which FSCN1 was knocked down. Atotal of 462 up and 601 downregulated mRNA transcripts were identified. Functional annotation analysis revealed that these DEGs were involved in multiple biological functions, such as transcriptional regulation, response to radiation, focal adhesion, extracellular matrix‑receptor interaction, steroid biosynthesis and others. Through co‑expression and protein‑protein interaction analysis, FSCN1 was linked to novel functions, including defense response to virus and steroid biosynthesis. Furthermore, crosstalk analysis with FSCN1‑interacting proteins revealed seven DEGs, identified as FSCN1‑interacting partners, in LSCC cells, three of which were selected for further validation. Co‑immunoprecipitation validation confirmed that FSCN1 interacted with prostaglandin reductase 1 and 24‑dehydrocholesterol reductase (DHCR24). Of note, DHCR24 is a key enzyme involved in cholesterol biosynthesis, and its overexpression promotes the proliferation and migration of LSCC cells. These findings suggest that DHCR24 is a novel molecule associated with FSCN1 in LSCC, and that the FSCN1‑DHCR24 interaction may promote LSCC progression by regulating cholesterol metabolism‑related signaling pathways.

KAT8/SIRT7-mediated Fascin-K41 acetylation/deacetylation regulates tumor metastasis in esophageal squamous cell carcinoma.

Fascin actin-bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F-actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin-mediated F-actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD-dependent protein deacetylase sirtuin (SIRT) 7-mediated deacetylation of Fascin-K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin-K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin-K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP-G2-044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP-G2-044 may be more suitable for patients with low levels of Fascin-K41 acetylation, but not suitable for patients with high levels of Fascin-K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Fascin actin-bundling protein 1 regulates non-small cell lung cancer progression by influencing the transcription and splicing of tumorigenesis-related genes

Background High mortality rates are prevalent among patients with non-small-cell lung cancer (NSCLC), and effective therapeutic targets are key prognostic factors. Fascin actin-bundling protein 1 (FSCN1) promotes NSCLC; however, its role as an RNA-binding protein in NSCLC remains unexplored. Therefore, we aimed to explore FSCN1 expression and function in A549 cells. Method We screened for alternative-splicing events and differentially expressed genes (DEGs) after FSCN1 silence via RNA-sequencing (RNA-seq). FSCN1 immunoprecipitation followed by RNA-seq were used to identify target genes whose mRNA expression and pre-mRNA alternative-splicing levels might be influenced by FSCN1. Results Silencing FSCN1 in A549 cells affected malignant phenotypes; it inhibited proliferation, migration, and invasion, and promoted apoptosis. RNA-seq analysis revealed 2,851 DEGs and 3,057 alternatively spliced genes. Gene ontology-based functional enrichment analysis showed that downregulated DEGs and alternatively splicing genes were enriched for the cell-cycle. FSCN1 promoted the alternative splicing of cell-cycle-related mRNAs involved in tumorigenesis (i.e., BCCIP, DLGAP5, PRC1, RECQL5, WTAP, and SGO1). Combined analysis of FSCN1 RNA-binding targets and RNA-seq data suggested that FSCN1 might affect ACTG1, KRT7, and PDE3A expression by modulating the pre-mRNA alternative-splicing levels of NME4, NCOR2, and EEF1D, that were bound to long non-coding RNA transcripts (RNASNHG20, NEAT1, NSD2, and FTH1), which were highly abundant. Overall, extensive transcriptome analysis of gene alternative splicing and expression levels was performed in cells transfected with FSCN1 short-interfering RNA. Our data provide global insights into the regulatory mechanisms associated with the roles of FSCN1 and its target genes in lung cancer.

Ginsenoside Rb2 inhibits p300-mediated SF3A2 acetylation at lysine 10 to promote Fscn1 alternative splicing against myocardial ischemic/reperfusion injury

IntroductionGinsenosides (GS) derived from Panax ginseng can regulate protein acetylation to promote mitochondrial function for protecting cardiomyocytes. However, the potential mechanisms of GS for regulating acetylation modification are not yet clear. ObjectivesThis study aimed to explore the potential mechanisms of GS in regulating protein acetylation and identify ginsenoside monomer for fighting myocardial ischemia-related diseases. MethodsThe 4D-lable free acetylomic analysis was employed to gain the acetylated proteins regulated by GS pretreatment. The co-immunoprecipitation assay, immunofluorescent staining, and mitochondrial respiration measurement were performed to detect the effect of GS or ginsenoside monomer on acetylated protein level and mitochondrial function. RNA sequencing, site-specific mutation, and shRNA interference were used to explore the downstream targets of acetylation modificationby GS. Cellular thermal shift assay and surface plasmon resonance were used for identifying the binding of ginsenoside with target protein. ResultsIn the cardiomyocytes of normal, oxygen glucose deprivation and/or reperfusion conditions, the acetylomic analysis identified that the acetylated levels of spliceosome proteins were inhibited by GS pretreatment and SF3A2 acetylation at lysine 10 (K10) was significantly decreased as a potential target of GS. Ginsenoside Rb2 was identified as one of the active ginsenoside monomers for reducing the acetylation of SF3A2 (K10), which enhanced mitochondrial respiration against myocardial ischemic injury in in vivo and in vitro experiments. RNA-seq analysis showed that ginsenoside Rb2 promoted alternative splicing of mitochondrial function-related genes and the level of fascin actin-bundling protein 1 (Fscn1) was obviously upregulated, which was dependent on SF3A2 acetylation. Critically, thermodynamic, kinetic and enzymatic experiments demonstrated that ginsenoside Rb2 directly interacted with p300 for inhibiting its activity. ConclusionThese findings provide a novel mechanism underlying cardiomyocyte protection of ginsenoside Rb2 by inhibiting p300-mediated SF3A2 acteylation for promoting Fscn1 expression, which might be a promising approach for the prevention and treatment of myocardial ischemic diseases.

FSCN1 Gene Expression Influence on Breast Cancer in Iraqi Patients

Our investigation aim was to ascertain how the Fascin actin-bundling protein 1 (FSCN1) gene affected breast cancer patients and how it affected the molecular type of the disease (Luminal A, Luminal B, Triple negative, Enrich Her2).By collecting blood samples from sixty patients with Breast cancer from many hospitals in Baghdad/Iraq between the periods (October 2021 to August 2022) and collecting forty volunteers heaths as Control. The volunteer's blood samples were collected and tested with Cancer antigen 15-3 (CA 15-3) to confirm absent breast cancer. The blood and control samples from these patients were collected, the RNA was extracted, and molecular methods using PCR and primers targeting the FSCN1 gene were used. The results showed that genes found in all patient samples have overexpression compared to healthy volunteers, and we also discovered differences in expression between the molecular types of breast cancer. We discovered that Triple-negative breast cancer is more affected than Luminal A, B, and Enrich Her2. Keywords: Breast Cancer, Molecular classification breast cancer, Fascin Actin Bundling protein 1 genes

Long noncoding RNA LGALS8-AS1 promotes angiogenesis and brain metastases in non-small cell lung cancer.

Brain metastases (BM) are associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). Considering that, LGAS8-AS1-mediated progression of BM was probed in NSCLC. The clinical characteristics of 60 NSCLC patients (30 without BM and 30 with BM) were analyzed. NSCLC patients with BM had higher levels of LGALS8-AS1 than NSCLC patients without BM. Depleting LGALS8-AS1 prevented NSCLC cell proliferation, migration, invasion, and angiogenesis in vitro, and NSCLC tumorigenesis and BM in vivo. LGALS8-AS1 targeted miR-885-3p to mediate Fascin actin-bundling protein 1 (FSCN1) expression. Restoring miR-885-3p inhibited NSCLC growth, angiogenesis, and BM, and FSCN1 induction rescued the performance of LGALS8-AS1 depletion on NSCLC cells. Our results provide new insights into LGALS8-AS1-mediated NSCLC metastasis and suggest that LGALS8-AS1 may be a useful biomarker for identifying NSCLC with metastatic potential.

FSCN1 promotes proliferation, invasion and glycolysis via the IRF4/AKT signaling pathway in oral squamous cell carcinoma

BackgroundOral squamous cell carcinoma (OSCC) is a disease with increasing incidence worldwide that leads to deformity and death. In OSCC, fascin actin-bundling protein 1 (FSCN1) is an oncogene involved in the tumorigenesis process. However, the functions and potential mechanisms of FSCN1 in the OSCC tumorigenesis process have not been reported thus far.MethodsWe used qRT‒PCR to detect the expression of FSCN1 in 40 paired OSCC tumor tissues (tumor) and neighboring noncancerous tissues. The role of FSCN1 was also assessed in vitro through colony formation, CCK-8, and transwell assays. Moreover, glucose consumption was detected. Western blotting was used to confirm the interaction of FSCN1, IRF4 and AKT.ResultsFSCN1 was remarkably overexpressed in OSCC tissues and cell lines compared to corresponding controls. In addition, colony formation, CCK-8, and transwell assays revealed a notable reduction in OSCC growth and invasion when FSCN1 was silenced. FSCN1 silencing remarkably suppressed OSCC glycolysis. Mechanistic studies showed that FSCN1 achieves its function partially by activating interferon regulatory factor 4 (IRF4) and the AKT pathway in OSCC.ConclusionIn conclusion, our study investigated the functions and mechanisms of the FSCN1/IRF4/AKT pathway in OSCC progression. In OSCC, FSCN1 is likely to be a biomarker and therapeutic target.

SYTL2 promotes metastasis of prostate cancer cells by enhancing FSCN1-mediated pseudopodia formation and invasion

BackgroundMetastatic prostate cancer (mPCa) has a poor prognosis with limited treatment options. The high mobility of tumor cells is the key driving characteristic of metastasis. However, the mechanism is complex and far from clarified in PCa. Therefore, it is essential to explore the mechanism of metastasis and discover an intrinsic biomarker for mPCa.MethodsTranscriptome sequencing data and clinicopathologic features of PCa from multifarious public databases were used to identify novel metastatic genes in PCa. The PCa tissue cohort containing 102 formalin-fixed paraffin-embedded (FFPE) samples was used to evaluate the clinicopathologic features of synaptotagmin-like 2 (SYTL2) in PCa. The function of SYTL2 was investigated by migration and invasion assays and a 3D migration model in vitro and a popliteal lymph node metastasis model in vivo. We performed coimmunoprecipitation and protein stability assays to clarify the mechanism of SYTL2.ResultsWe discovered a pseudopodia regulator, SYTL2, which correlated with a higher Gleason score, worse prognosis and higher risk of metastasis. Functional experiments revealed that SYTL2 promoted migration, invasion and lymph node metastasis by increasing pseudopodia formation in vitro and in vivo. Furthermore, SYTL2 induced pseudopodia formation by enhancing the stability of fascin actin-bundling protein 1 (FSCN1) by binding and inhibiting the proteasome degradation pathway. Targeting FSCN1 enabled rescue and reversal of the oncogenic effect of SYTL2.ConclusionsOverall, our study established an FSCN1-dependent mechanism by which SYTL2 regulates the mobility of PCa cells. We also found that the SYTL2-FSCN1-pseudopodia axis may serve as a pharmacological and novel target for treating mPCa.

FSCN1 as a new druggable target in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high risk of relapse and metastatic spread. The actin-bundling protein fascin (FSCN1) is overexpressed in aggressive ACC and represents a reliable prognostic indicator. FSCN1 has been shown to synergize with VAV2, a guanine nucleotide exchange factor for the Rho/Rac GTPase family, to enhance the invasion properties of ACC cancer cells. Based on those results, we investigated the effects of FSCN1 inactivation by CRISPR/Cas9 or pharmacological blockade on the invasive properties of ACC cells, both in vitro and in an in vivo metastatic ACC zebrafish model. Here, we showed that FSCN1 is a transcriptional target for β-catenin in H295R ACC cells and that its inactivation resulted in defects in cell attachment and proliferation. FSCN1 knock-out modulated the expression of genes involved in cytoskeleton dynamics and cell adhesion. When Steroidogenic Factor-1 (SF-1) dosage was upregulated in H295R cells, activating their invasive capacities, FSCN1 knock-out reduced the number of filopodia, lamellipodia/ruffles and focal adhesions, while decreasing cell invasion in Matrigel. Similar effects were produced by the FSCN1 inhibitor G2-044, which also diminished the invasion of other ACC cell lines expressing lower levels of FSCN1 than H295R. In the zebrafish model, metastases formation was significantly reduced in FSCN1 knock-out cells and G2-044 significantly reduced the number of metastases formed by ACC cells. Our results indicate that FSCN1 is a new druggable target for ACC and provide the rationale for future clinical trials with FSCN1 inhibitors in patients with ACC.

The actin bundling protein Fascin is important for proper early development in Strongylocentrotus purpuratus embryos.

Fascin is a conserved protein that has been shown to modulate the cytoskeleton. Its role in early development remains unclear. After fertilization, embryos undergo rapid cell divisions, requiring the precise regulation of cytoskeleton to segregate chromosomes. Results indicate that Fascin is in the cell cortex, enriched in the perinuclear region of non-dividing blastomeres and on the mitotic spindle of dividing blastomeres of the early embryo. Loss-of-function of Fascin leads to a significant developmental delay or arrest, indicating that Fascin is important for proper early embryonic development.

FSCN1 induced PTPRF-dependent tumor microenvironment inflammatory reprogramming promotes lung adenocarcinoma progression via regulating macrophagic glycolysis.

Macrophages (MΦs) play a dual role in the promotion and suppression of lung adenocarcinoma (LUAD), the function of which is influenced by the metabolic status. The role of protein tyrosine phosphatase receptor type F (PTPRF) in cancer has not been elucidated, and its role in MΦs remains to be seen. The Seahorse XFe 96 Cell Flow Analyzer detected glucose metabolism in tumor cells and macrophages. The expressions of FSCN1, M-CSF, IL4, PTPRF and IGF1 in macrophages were detected by Western blotting and qRT-PCR. Binding of FSCN1 and IGF1R was detected by co-immunoprecipitation. The tumor status in animals was observed using the IVIS Lumina III imaging system. We found that Fascin Actin-Bundling Protein 1 (FSCN1) activates the PI3K-AKT and JAK-STAT signaling pathways in LUAD cells via binding to IGF-1R, thereby promoting the secretion of cytokines such as IL4 and M-CSF. IL4 and M-CSF promote the expression of PTPRF in MΦs, leading to M2 polarization of MΦs by increasing glucose intake and lactate production. In return, M2-type MΦs act on LUAD cells by secreting cytokines such as IGF-1, CCL2, and IL10, which ultimately promote tumor progression. In vivo experiments proved that the knockdown of FSCN1 in A549 cells and PTPRF in MΦs greatly reduced LUAD proliferative and metastatic capacity, which was consistent with the in vitro findings. This study investigated the reprogramming effects of FSCN1 and PTPRF on inflammatory cytokines in the LUAD microenvironment, revealing potential mechanisms by which FSCN1 and PTPRF promote tumor progression and providing a new experimental basis for LUAD treatment.

Long noncoding RNA CDKN2B-AS1 silencing protects against esophageal cancer cell invasion and migration by inactivating the TFAP2A/FSCN1 axis.

Esophageal cancer (EC) is the most aggressive malignancy in the gastrointestinal tract. Long noncoding RNA cyclin-dependent kinase inhibitor 2 B antisense RNA 1 (CDKN2B-AS1) is implicated in EC development. However, the specific mechanisms involved remain poorly defined. Therefore, this research aimed to explore the mechanism of action of CDKN2B-AS1 in EC. Quantitative real-time polymerase chain reaction was conducted to measure CDKN2B-AS1 expression in EC cells and western blotting was utilized to evaluate transcription factor AP-2 alpha (TFAP2A) and fascin actin-bundling protein 1 (FSCN1) expression. After gain-of-function and loss-of-function assays, cell proliferation, migration, invasion, apoptosis, and apoptosis-related protein expression were assessed using cell counting kit-8, scratch tests, Transwell assays, flow cytometry, and western blotting, respectively. The binding relationship between CDKN2B-AS1 and TFAP2A was assessed by RNA immunoprecipitation and RNA pull-down assays. The binding relationship between TFAP2A and FSCN1 was evaluated using dual-luciferase reporter and chromatin immunoprecipitation assays. Tumor xenografts from nude mice were used for in vivo verification. CDKN2B-AS1, TFAP2A, and FSCN1 were upregulated in EC cells. Mechanistically, CDKN2B-AS1 transcriptionally activated FSCN1 by recruiting TFAP2A to the FSCN1 promoter. Silencing CDKN2B-AS1 or TFAP2A suppressed EC cell proliferative, migrating, and invasive properties and augmented apoptosis. TFAP2A was bound to CDKN2B-AS1 and the FSCN1 promoter. Overexpression of TFAP2A or FSCN1 abolished the effects of CDKN2B-AS1-silencing on EC cell function. CDKN2B-AS1 silencing curtailed tumorigenesis in nude mice, which was nullified by the upregulation of TFAP2A or FSCN1. Our findings demonstrated the antioncogenic effects of silencing CDKN2B-AS1 in EC through inactivation of the TFAP2A/FSCN1 axis.

The post-translational modification of Fascin: impact on cell biology and its associations with inhibiting tumor metastasis.

The post-translational modifications (PTMs), which are crucial in the regulation of protein functions, have great potential as biomarkers of cancer status. Fascin (Fascin actin-bundling protein 1, FSCN1), a key protein in the formation of filopodia that is structurally based on actin filaments (F-actin), is significantly associated with tumor invasion and metastasis. Studies have revealed various regulatory mechanisms of human Fascin, including PTMs. Although a number of Fascin PTM sites have been identified, their exact functions and clinical significance are much less explored. This review explores studies on the functions of Fascin and briefly discusses the regulatory mechanisms of Fascin. Next, to review the role of Fascin PTMs in cell biology and their associations with metastatic disease, we discuss the advances in the characterization of Fascin PTMs, including phosphorylation, ubiquitination, sumoylation, and acetylation, and the main regulatory mechanisms are discussed. Fascin PTMs may be potential targets for therapy for metastatic disease.

Prognostic Factors for Recurrence in Pituitary Adenomas: Recent Progress and Future Directions.

Pituitary adenomas (PAs) are benign lesions; nonetheless, some PAs exhibit aggressive behaviors, which lead to recurrence. The impact of pituitary dysfunction, invasion-related risks, and other complications considerably affect the quality of life of patients with recurrent PAs. Reliable prognostic factors are needed for recurrent PAs but require confirmation. This review summarizes research progress on two aspects—namely, the clinical and biological factors (biomarkers) for recurrent PAs. Postoperative residue, age, immunohistological subtypes, invasion, tumor size, hormone levels, and postoperative radiotherapy can predict the risk of recurrence in patients with PAs. Additionally, biomarkers such as Ki-67, p53, cadherin, pituitary tumor transforming gene, matrix metalloproteinase-9, epidermal growth factor receptor, fascin actin-bundling protein 1, cyclooxygenase-2, and some miRNAs and lncRNAs may be utilized as valuable tools for predicting PA recurrence. As no single marker can independently predict PA recurrence, we introduce an array of comprehensive models and grading methods, including multiple prognostic factors, to predict the prognosis of PAs, which have shown good effectiveness and would be beneficial for predicting PA recurrence.

FSCN1 Promotes Esophageal Carcinoma Progression Through Downregulating PTK6 via its RNA-Binding Protein Effect.

Objective: Esophageal squamous cell carcinoma (ESCC) causes many deaths worldwide every year. Fascin actin-bundling protein 1(FSCN1) has been reported to be a promoter of ESCC via its actin-binding function, however, its new role as an RNA-binding protein (RBP) has not been investigated. Here, we explored the RBP role of FSCN1 in the development of ESCC. Methods: Whole-genome expression sequencing was performed to screen for altered genes after FSCN1 knockdown. RNA immunoprecipitation was performed to determine the target mRNA of FSCN1 as an RBP. In vitro experiments with ECA-109 and KYSE-150 and ex vivo experiments in tumor-bearing mice were performed to investigate the effects of FSCN1 and Protein Tyrosine Kinase 6 (PTK6) on ESCC progression. Results: FSCN1 could downregulate mRNA and the protein level of PTK6. The binding position of PTK6 (PTK6-T2) pre-mRNA to FSCN1 was determined. PTK6-T2 blocked the binding between FSCN1 and the pre-mRNA of PTK6, and thus reversed the promotion effect of FSCN1 on ESCC tumor progression via the AKT/GSK3β signaling pathway. Conclusion: A novel effect of FSCN1, RBP-binding with the pre-mRNA of PTK6, was confirmed to play an important role in ESCC progression. PTK6-T2, which is a specific inhibitor of FSCN1 binding to the pre-mRNA of PTK6, could impede the development of ESCC.

Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma.

Lineage dedifferentiation toward a mesenchymal‐like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and acquired resistance to targeted therapy in melanoma. Here, we show that the anti‐fibrotic drug nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK‐targeted therapy, and delay tumor relapse in a preclinical model of melanoma. Acquisition of this resistant phenotype and its reversion by nintedanib pointed to miR‐143/‐145 pro‐fibrotic cluster as a driver of this mesenchymal‐like phenotype. Upregulation of the miR‐143/‐145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile. The 2 mature miRNAs generated from this cluster, miR‐143‐3p and miR‐145‐5p, collaborated to mediate transition toward a drug‐resistant undifferentiated mesenchymal‐like state by targeting Fascin actin‐bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics and mechanotransduction pathways. Our study brings insights into a novel miRNA‐mediated regulatory network that contributes to non‐genetic adaptive drug resistance and provides proof of principle that preventing MAPKi‐induced pro‐fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.

Transcriptome analysis reveals the potential biological function of FSCN1 in HeLa cervical cancer cells.

Fascin actin-bundling protein 1 (FSCN1), an actin-bundling protein associated with cell migration and invasion, is highly expressed in various tumor tissues. FSCN1 has also been reported to be a marker of increased invasive potential in cervical cancers. However, the functions of FSCN1 are still not fully understood in cervical cancers. Here, the gene expression profile of HeLa cells transfected with FSCN1 shRNA (shFSCN1) was compared with that of cells transfected with empty vector (shCtrl). The results showed that shFSCN1 extensively affected the transcription level of 5,043 genes in HeLa cells. In particular, Gene Ontology (GO) analysis showed that a large number of upregulated genes were annotated with terms including transcription regulation and DNA binding. The downregulated genes were enriched in some cancer pathways, including angiogenesis and cell adhesion. qPCR validation confirmed that FSCN1 knockdown significantly affected the expression of selected genes in HeLa cells either negatively or positively. Expression analysis in TCGA (The Cancer Genome Atlas) revealed that FSCN1 had negative correlations with several transcription factors and a positive correlation with an angiogenic factor (angiopoietin like 4, ANGPTL4) in cervical tumor tissue. In particular, validation by Western blotting showed that FSCN1 knockdown decreased the protein level of ANGPTL4. Our results demonstrated that FSCN1 is not only an actin-binding protein but also a transcriptional regulator and an angiogenic factor in cervical cancer. Thus, our study provides important insights for further study on the regulatory mechanism of FSCN1 in cervical cancer.

Fascin enhances the vulnerability of breast cancer to erastin-induced ferroptosis

Ferroptosis, which is characterized by intracellular iron accumulation and lipid peroxidation, is a newly described form of regulated cell death that may play a key role in tumour suppression. In the present study, we investigated the expression profiles and biological effects of fascin actin-bundling protein 1 (Fascin, gene name FSCN1) in breast cancer. In addition, bioinformatics analysis of the TCGA cancer database and gain- and loss-of-function studies showed that Fascin enhances sensitivity to erastin-induced ferroptosis. Mechanistically, Fascin directly interacts with cysteine/glutamate transporter (xCT, gene name SLC7A11) and decreases its stability via the ubiquitin-mediated proteasome degradation pathway. Furthermore, we observed that Fascin is substantially upregulated in tamoxifen-resistant breast cancer cell lines, and drug-resistant cells were also more vulnerable to erastin-induced ferroptosis. Taken together, our findings reveal a previously unidentified role of Fascin in ferroptosis by regulating xCT. Thus, ferroptosis activation in breast cancer with high Fascin level may serve as a potential treatment.

Alternative NF-κB Signaling Discriminates Induction of the Tumor Marker Fascin by the Viral Oncoproteins Tax-1 and Tax-2 of Human T-Cell Leukemia Viruses.

Simple SummaryThe actin-bundling protein Fascin is upregulated in many types of cancers, including adult T-cell leukemia/lymphoma, a tumor induced by the oncogenic retrovirus human T-cell leukemia virus type 1 (HTLV-1). Transcriptional regulation of Fascin is heterogeneous between different cell types and tissues, and Fascin is usually expressed at low levels in T-cells. We have previously shown that a single viral oncoprotein, Tax-1 of HTLV-1, is a potent inducer of Fascin in T-cells depending on classical NF-κB signaling. In this study, we discovered that transcriptional activation of Fascin by viral oncoproteins depends on activity of both the classical and the alternative NF-κB signaling cascade. Comparisons between Tax-1 and Tax-2 from the closely related but non-oncogenic HTLV-2 revealed that alternative NF-κB signaling discriminates transcriptional induction of Fascin by the Tax proteins encoded by HTLVs. Together, Tax-1 and Tax-2 proteins are useful tools to study oncogenic signaling in T-cells.Transcriptional regulation of the actin-bundling protein and tumor marker Fascin is highly diverse depending on cell and tumor type. Previously, we discovered that the viral oncoprotein Tax-1 of human T-cell leukemia virus type 1 (HTLV-1) considerably enhances Fascin expression in T-cells, depending on classical NF-κB signaling. In this study, we asked if the non-oncogenic Tax-2 of the related HTLV-2 is still able to induce Fascin by using luciferase assays, immunoblot, and qPCR. We found that Tax-2 only slightly induces Fascin expression compared to Tax-1; however, both Tax-1 and Tax-2 comparably activated a 1.6 kb fragment in the human Fascin promoter including Tax-responsive elements. Furthermore, we identified a link between Tax-induced activity of the alternative NF-κB pathway and Fascin induction. While treatment with the second mitochondria-derived activator of caspases (SMAC)-mimetic AZD5582, a compound known to robustly activate alternative NF-κB signaling, did not induce Fascin, combination of AZD5582 with activation of classical NF-κB signaling by Tax-2 significantly induced Fascin expression. In conclusion, our data demonstrate that both classical and alternative NF-κB activity are necessary for strong Fascin induction by the viral Tax oncoproteins, thus, shedding new light on the regulation of Fascin in T-cells and during viral transformation.

FSCN1 acts as a promising therapeutic target in the blockade of tumor cell motility: a review of its function, mechanism, and clinical significance.

Fascin actin-bundling protein 1 (FSCN1) is an actin-bundling protein that is capable of inducing membrane protrusions and plays critical roles in cell migration, motility, adhesion, and other cellular interactions. FSCN1 also plays a role in forming and stabilizing filopodia or microspikes, which assist during cell migration. Furthermore, FSCN1 is a downstream target of several microRNAs and participates in various biological processes, such as epithelial-to-mesenchymal transition and autophagy, which regulate the invasion and migration ability of cells in various cancers. Increased FSCN1 levels have been associated with enhanced migration and invasion of multiple cancers as well as poor patient prognosis. Promising results from in vitro experimental studies using docosahexaenoic acid (DHA) in breast cancer and recombinant porcine NK-lysin A in hepatocellular carcinoma have revealed that anticancer drugs targeting FSCN1 have significant potential clinical applications. This review discusses FSCN1 in terms of five aspects: structure and function, biological processes, regulatory mechanisms, clinical applications, and future prospects.