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. 2022 May 17;2:100052. doi: 10.1016/j.bbadva.2022.100052

Fascin-1: Updated biological functions and therapeutic implications in cancer biology

Chien-Hsiu Li a,#, Ming-Hsien Chan a,#, Shu-Mei Liang b, Yu-Chan Chang c,⁎, Michael Hsiao a,d,⁎
PMCID: PMC10074911  PMID: 37082587

Highlights

  • •

    A comprehensive, integrated clinical trial was beneficial for understanding the roles of the Fascin family across cancers.

  • •

    Several noncanonical Fascin-1 functions have been associated with cancer progression.

  • •

    A systematic molecular mechanism illustrates how tumor cells interact with their microenvironment through Fascin-1.

  • •

    The potential treatment of Fascin-1 is beneficial for developing translational medicines to inhibit the progression of cancer.

Keywords: FSCN, Fascin, Cancer, Bioinformatics

Abstract

Filopodia are cellular protrusions that respond to a variety of stimuli. Filopodia are formed when actin is bound to the protein Fascin, which may play a crucial role in cellular interactions and motility during cancer metastasis. Significantly, the noncanonical features of Fascin-1 are gradually being clarified, including the related molecular network contributing to metabolic reprogramming, chemotherapy resistance, stemness ac-tivity, and tumor microenvironment events. However, the relationship between biological characteristics and pathological features to identify effective therapeutic strategies needs to be studied further. The pur-pose of this review article is to provide a broad overview of the latest molecular networks and multiomics research regarding fascins and cancer. It also highlights their direct and indirect effects on available cancer treatments. With this multidisciplinary approach, researchers and clinicians can gain the most relevant in-formation on the function of fascins in cancer progression, which may facilitate clinical applications in the future.

Graphical abstract

Image, graphical abstract

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1. Introduction

Cellular plasticity makes cells respond to extracellular stimuli. This is accompanied by morphological changes to interactions or motility, which are involved in complex signal transduction to remodel the cytoskeleton. To attain such changes, cells rearrange actin filaments by actin-bundling proteins. For example, Fascin proteins, approximately 55–58 kDa, have been widely regarded as the molecules most involved in the regulation of the cytoskeleton. The first complete characterization was in 1979. It was discovered to be related to the morphology of filopodia formation in the sea urchin, opening up research into exploring the relationship between Fascin and the molecular mechanism of action of cells [1]. The protein is mainly composed of four β-trefoil structure loops connected, which exposes the F-actin-binding site. The crosslinking between Fascin and f-actin consequently changes cell morphology into filopodia, lamellipodia, stress fibers, and microspike structures, causing cells to undergo motility processes. Cellular migration is involved in multiple biological events, including embryogenesis, wound healing, and carcinogenesis. In cancer, migration and invasion have been defined as hallmarks that cause the patient to be diagnosed at an advanced stage with more rapid progression. The critical role of Fascin-1 has been recognized to contribute to cancer progression. However, most of the research is mainly based on Fascin-1, and other members, including Fascin-2 and Fascin-3, which are linked to pathological features, remain largely unknown. Therefore, this review summarizes the current research related to Fascin-1, enriched with omics-related data, to redefine their significance in cancer.

Currently, three members are classified by their relative sequence in the Fascin family. The related protein sequences between fascins revealed their possible evolutionary lineage relationship and diverse protein motif consensus sequence, including the beta-strand, helix, modified residue, turn, and similarity in humans (Fig. 1). They even share a similar protein sequence. However, the distribution and relative biology were distinct from each other. Based on the RNA and protein expression, Fascin-1 participates in more biological functions in the human body (Fig. 2). According to the distribution of Fascin-1 in organs, it is predictably involved in multiple biological functions.

Fig. 1.

Fig. 1

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Evolution lineage of the Fascin family.

Information on the Fascin family was generated from the UniProt website, and the consensus sequence or diverse protein motifs are highlighted with different colors.

Fig. 2.

Fig. 2

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The relative distribution of the Fascin family in human organs.

The relative Fascin 1-3 distributions are highlighted with different colors, including RNA and protein levels in human organs. Levels of RNA and protein were provided from the human protein atlas datasets and organized according to the related location. NX: Normalized expression, N/A: not applicable.

1.1. Fascin-1

1.1.1. Embryogenesis

During embryogenesis, oocyte meiotic maturation was associated with the interaction of FNNL3 and Fascin-1 [2,3]. A similar phenomenon was observed in endoderm formation, which can be regulated by the interaction of the TGF-β receptor and Fascin-1 to control receptor trafficking into early endosomes [4]. During neurogenesis, the mRNA expression of Fascin-1 can be observed to increase and is governed by CREB-binding protein and retinoic acid [5]. The related expression of Fascin-1 was associated with spermatid maturation, morphology, and motility [6,7]. A similar association was found in oral dysplasia and linked to carcinoma in situ [8]. In addition, the self-renewal ability of hematopoietic stem cells can be regulated by the TSC1/2-Fascin-1 axis [9]. Interestingly, the level of Fascin-1 is correlated with skeletogenesis and can serve as a meat production trait [10,11]. Most importantly, Fascin-1 contributes to hepatoblast and neuroblast migration into the proper location to form the liver and ​interneurons in the olfactory bulb [12,13].

1.1.2. Tissue repair

Fascin-1 is difficult to detect in normal colon tissues, and excessive Fascin-1 may be seen in inflammatory bowel disease tissues, which may be due to tissue injury or repair [14]. Wang et al. observed that the IL-6-mediated AKT/GSK 3β/β-catenin/Fascin-1 axis drove cell migration to remodel or repair the airway [15]. Therefore, targeting Fascin-1 may provide alternative strategies for asthma. A similar phenomenon was observed in spinal cord injury [16]. Miao et al. provided a possible mechanism in which SOX4 and SOX11 can reactivate Fascin-1 to undergo an epithelial and mesenchymal transition (EMT) to participate in the wound repair process [17].

1.1.3. Fibrogenesis

Such processes can be observed in tissue fibrosis. Zhang and Fu et al. observed that Fascin-1 participated in fibrogenesis processes and was regulated by miR-145-5p or miR-200b/c [18,19].

1.1.4. Motility

In addition, the phosphorylation of Fascin-1 at serine 39 can be induced by IL-17A, resulting in airway smooth muscle contraction [20].

1.1.5. Immune response

Moreover, Fascin-1 can serve as an immune response factor. The related expression of Fascin-1 was correlated with the level of autoimmune neuritis [21]. For example, the dendritic cell level is considered an inductor of allograft rejection when patients undergo transplantation. Yang et al. found that Fascin-1 presented in dendritic cells may contribute to related events [21] and may be used as a diagnostic indicator for patients treated with immunosuppression inhibitors [22]. A similar incidence of dendritic cells can be observed in allogeneic hematopoietic stem cell transplantation [23]. Targeting circFSCN1 can prevent alloimmune rejection in heart transplantations [24]. Conversely, Staphylococcus aureus-induced mastitis can be prevented by restoring Fascin-1 [25]. Moreover, the expression of Fascin-1 in dendritic cells responded to virus-infected events, such as human immunodeficiency virus-related lymphoid hyperplasias [26]. Interestingly, dendritic cell activity can be restricted by regulatory T cells through Fascin-1 [27].

1.1.6. Carcinogenesis

Most importantly, the expression of Fascin-1 in dendritic cells can serve as a distinguishing marker for Epstein–Barr virus-mediated Hodgkin's disease [28,29] and may contribute to its pathogenesis [30]. A similar phenomenon was observed in nasal inverted papilloma [31], which indicates that Fascin-1 links diverse diseases, including cancer progression.

1.2. Fascin-2

Fascin-2 has been found to be related to the functions of the ears and eyes.

1.2.1. Eye development

Fascin-2 has been found to be related to the functions of the ears and eyes. The genetic heterogeneity associated with retinitis pigmentosa, such as autosomal dominant retinitis pigmentosa and macular dystrophy, may be linked to mutations in Fascin-2 [32,33]. In a murine model, the 208delG/R109H mutation in Fascin-2 was positively linked to progressive photoreceptor degeneration [34]. Mechanistically, the phosphorylation of serine 39 can stabilize the actin cytoskeleton in the inner segment, consequently regulating photoreceptor disk morphogenesis [35].

1.2.2. Development

In addition, Lv et al. found that premRNA splicing factors may control the level of Fascin-2, causing retinitis pigmentosa [36]. In addition, mutation of Fascin-2 contributes to age-related hearing loss [37], [38], [39]. Such mutation can induce caspase-3-mediated apoptosis, resulting in progressive hair cell loss and spiral ganglion neuron degeneration [40].

1.3. Fascin-3

1.3.1. Spermatogenesis

Currently, testis-specific expressed Fascin-3 was found to be related to spermatogenesis and microfilament rearrangements [41]. It has also been demonstrated that Fascin-3-mediated spermatogenesis can be regulated by vitamin E [42], and treatment with methotrexate and platelet-rich plasma can upregulate the level of Fascin-3, which may be linked to the regeneration of testicular tissue [43].

As described above, the Fascin family plays an essential role from embryogenesis to disease development, in which Fascin-1 contributes to diverse biological processes after embryogenesis. However, Fascin-2 and Fascin-3 were assumed to only function during embryogenesis. Therefore, most studies have focused on Fascin-1. However, based on the Fascin family's biological distribution, they may partially share similar functions with each other (Fig. 3). Such hypotheses may be supported by Deng et al., who found that Fascin-1 and Fascin-2 were correlated with favorable overall survival in multiple myeloma, which indicated that the submembers might compensate for the functions [44]. Therefore, the unknown molecular interaction between the Fascin family may provide a possible niche and valuable biological processes that should be explored, especially in cancer biology.

Fig. 3.

Fig. 3

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Current understanding of the biological functions within the Fascin family.

The related biological functions of each Fascin submember were organized based on the works cited in the literature.

1.4. Fascin-1: Current understanding of the molecular network in cancers

The Cancer Genome Atlas Program datasets have been used to correlate cancer prognosis and provide a comparable analysis between family members. The correlation of Fascin and patient expression and overall survival rates across cancers are listed in Table 1, which provides insight into cancer development. Based on these correlations, it is suggested that Fascin-2 and Fascin-3 might be linked to cancer progression and worth exploring. However, no specific study has explored the relationship between them and cancer. Until now, Fascin-1 has been identified as being linked to cancer progression (Table 2). Therefore, the updated molecular networks of Fascin-1 that contribute to cancer are detailed in the following sections.

Table 1.

The relationship between the overall survival rate and FSCN family.

FSCN1
 FSCN2
 FSCN3
Cancer type Endpoint Case Cohort p-value Log-rank test statistics Risk p-value Log-rank test statistics Risk p-value Log-rank test statistics Risk
Acute Myeloid Leukemia (LAML) Overall survival 161 TCGA 0.8556 0.03311 High 0.7654 0.08902 High 0.9216 0.009675 Low
Adrenocortical Cancer (ACC) Overall survival 79 TCGA 0.000008006 19.94 High 0.01814 5.582 High 0.8998 0.01586 High
Bile Duct Cancer (CHOL) Overall survival 45 TCGA 0.8954 0.01729 High 0.01858 5.541 Low 0.4946 0.4665 High
Bladder Cancer (BLCA) Overall survival 425 TCGA 0.08484 2.97 High 0.7967 0.06637 Low 0.7141 0.1342 Low
Breast Cancer (BRCA) Overall survival 1214 TCGA 0.7528 0.09919 Low 0.0003311 12.89 Low 0.6949 0.1538 High
Cervical Cancer (CESC) Overall survival 307 TCGA 0.09286 2.824 High 0.7861 0.07362 High 0.234 1.416 High
Colon and Rectal Cancer (COADREAD) Overall survival 250 TCGA 0.07314 3.211 High 0.0426 4.111 High 0.5161 0.4217 High
Colon Cancer (COAD) Overall survival 326 TCGA 0.0301 4.704 High 0.03691 4.354 High 0.178 1.814 High
Endometrioid Cancer (UCEC) Overall survival 189 TCGA 0.2443 1.356 High 0.1384 2.196 High 0.5209 0.4121 High
Esophageal Cancer (ESCA) Overall survival 196 TCGA 0.8227 0.0502 High 0.5332 0.3883 High 0.8606 0.03085 Low
Glioblastoma (GBM) Overall survival 166 TCGA 0.9675 0.001656 Low 0.2284 1.451 High 0.9988 0.000002288 High
Head and Neck Cancer (HNSC) Overall survival 565 TCGA 0.0313 4.637 High 0.8648 0.02898 High 0.7678 0.08714 High
Kidney Chromophobe (KICH) Overall survival 89 TCGA 0.3003 1.073 Low 0.5292 0.3959 Low 0.6487 0.2075 Low
Kidney Clear Cell Carcinoma (KIRC) Overall survival 606 TCGA 0.03181 4.609 High 0.006612 7.375 High 0.0253 5.003 High
Kidney Papillary Cell Carcinoma (KIRP) Overall survival 322 TCGA 0.3914 0.7346 Low 0.4047 0.6944 Low 0.7855 0.0741 Low
Large B-cell Lymphoma (DLBC) Overall survival 48 TCGA 0.3779 0.7775 Low 0.3381 0.9175 High 0.6996 0.1489 Low
Liver Cancer (LIHC) Overall survival 422 TCGA 0.1047 2.633 High 0.4772 0.5053 High 0.3422 0.902 High
Lower Grade Glioma (LGG) Overall survival 528 TCGA 0.07948 3.075 High 0.001565 10 High 0.9924 0.00008962 Low
lower grade glioma and glioblastoma (GBMLGG) Overall survival 694 TCGA 0.00E+00 42.8 High 0.00E+00 39.32 High 0.00E+00 35.64 High
Lung Adenocarcinoma (LUAD) Overall survival 567 TCGA 0.004941 7.901 High 0.3183 0.9959 Low 0.003331 8.617 Low
Lung Cancer (LUNG) Overall survival 1062 TCGA 0.005903 7.58 High 0.7667 0.08801 High 0.1034 2.653 Low
Lung Squamous Cell Carcinoma (LUSC) Overall survival 495 TCGA 0.9843 0.0003853 Low 0.2124 1.555 High 0.9689 0.001519 High
Melanoma (SKCM) Overall survival 457 TCGA 0.2627 1.255 Low 0.002391 9.222 Low 0.0715 3.248 High
Mesothelioma (MESO) Overall survival 86 TCGA 0.00007813 15.6 High 0.4645 0.535 High 0.699 0.1496 Low
Ocular melanomas (UVM) Overall survival 80 TCGA 0.9311 0.007473 High 0.3393 0.913 High 0.5495 0.3582 Low
Ovarian Cancer (OV) Overall survival 307 TCGA 0.2355 1.408 High 0.1991 1.649 High 0.8905 0.01894 Low
Pancreatic Cancer (PAAD) Overall survival 183 TCGA 0.06491 3.407 High 0.06578 3.385 Low 0.01428 6.004 Low
Pheochromocytoma & Paraganglioma (PCPG) Overall survival 187 TCGA 0.07147 3.249 Low 0.01778 5.618 Low 0.5271 0.4 Low
Prostate Cancer (PRAD) Overall survival 550 TCGA 0.9567 0.00295 High 0.3856 0.7528 Low 0.4765 0.5068 high
Rectal Cancer (READ) Overall survival 58 TCGA 0.8169 0.05361 Low 0.2931 1.105 High 0.3266 0.9625 Low
Sarcoma (SARC) Overall survival 265 TCGA 0.01546 5.864 High 0.08581 2.951 Low 0.01136 6.408 Low
Stomach Cancer (STAD) Overall survival 443 TCGA 0.338 0.9179 High 0.7561 0.0965 High 0.8238 0.04955 high
Testicular Cancer (TGCT) Overall survival 139 TCGA 0.5686 0.3249 Low 0.4313 0.6193 High 0.0644 3.42 Low
Thymoma (THYM) Overall survival 121 TCGA 0.09627 2.766 High 0.4999 0.4551 High 0.3964 0.7191 Low
Thyroid Cancer (THCA) Overall survival 572 TCGA 0.1477 2.096 High 0.2651 1.242 High 0.7129 0.1354 high
Uterine Carcinosarcoma (UCS) Overall survival 57 TCGA 0.2991 1.078 Low 0.474 0.5126 Low 0.346 0.8879 Low
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The correlation between the Fascin family and patients with cancer is listed based on “The Cancer Genome Atlas Program” generated from the XENA websites.

Table 2.

Related Fascin-1 studies in cancers.

Cancer type FSCNs expression Biological relevance Model Year Author Reference
Breast cancer FSCN1 Diagnosis biomarker Human Specimens 2000 A Grothey [45]
Associated with tumors motility and malignancy MDA-MB-435 2000 A Grothey [46]
Insulin-like growth factor-I receptor-induced Fascin projections Cell lines (HMEC, BT474, MDA-MB-231, MCF-7) 2000 Marina A Guvakova [47]
Diagnosis biomarker Human Specimens 2005 Brian J Yoder [48]
Diagnosis biomarker Human Specimens 2006 Socorro María Rodríguez-Pinilla [49]
Diagnosis biomarker Human Specimens 2010 Y Zhang [50]
Regulation of tumor cell proliferation and motility Cell lines (MDA-MB-435, MDA-MB-231, T-47D) 2011 Peng Xing [51]
Regulation of tumor cell motility Human Specimens, Cell lines (MDA-MB-23, T-47D) 2011 Monther Al-Alwan [52]
Diagnosis biomarker Human Specimens 2014 Ashwini K Esnakula [53]
Diagnosis biomarker Human Specimens 2014 Nermeen Salah Youssef [54]
Chemoresistant Cell lines (MDA-MB-231, SK-BR-3, and T-47D) 2014 H Ghebeh [55]
Regulation of tumor cell motility Cell lines (MDA-MB-231) 2014 Marylynn Snyder [56]
Diagnosis biomarker Human Specimens 2015 Kyueng-Whan Min [57]
Diagnosis biomarker Human Specimens 2015 Ola M Omran [58]
Diagnosis biomarker Human Specimens 2016 Chao-Qun Wang [59]
Stemness activity Cell lines (MDA-MB-231, T-47D) 2016 Rayanah Barnawi [60]
Regulation of tumor cell motility Human Specimens, Cell lines (MDA-MB-231, MDA-MB-468, and MCF-7) 2017 Chao-Qun Wang [61]
Diagnosis biomarker Human Specimens 2017 Hye Jin Lee [62]
Regulation of tumor cell metastasis Cell lines (MDA-MB-231) 2017 Lisa S Heinz [63]
Diagnosis biomarker Human Specimens 2019 Ata Abbasi [64]
Diagnosis biomarker Human Specimens 2019 Ekaterini Christina Tampaki [65]
Stemness activiry Cell lines (MDA-MB-231, T-47D) 2020 Rayanah Barnawi [66]
Ovarian cancer FSCN1 Diagnosis biomarker Patient-derived cells, Human tissues 2000 W Hu [67]
Diagnosis biomarker Human Specimens 2008 Alexandros Daponte [68]
Diagnosis biomarker Human Specimens 2008 Chih-kung Lin [69]
Diagnosis biomarker Human Specimens 2009 Chih-Kung Lin [69]
Diagnosis biomarker Human Specimens 2013 Lars C Hanker [69]
Regulation of tumor cell metastasis Human Specimens, Cell lines (HeyA8, Ovcar5, Tyk-nu, Snu119, and Kuramochi) 2019 Sean McGuire [70]
Regulation of tumor cell motility Cell lines (ES-2, SK-OV-3 and NOE) 2020 Masato Yoshihara [71]
Pancreatic cancer FSCN1 Diagnosis biomarker Human Specimens 2002 Anirban Maitra [72]
Diagnosis biomarker Human Specimens 2004 Sharon L Swierczynski [73]
Regulation of tumor cell motility Cell lines (BxPC-3, MIAPaCa-2,AsPC-, PC-1, PC-4 and PC-7) 2011 Yan-Feng Xu [74]
Diagnosis biomarker Human Specimens 2013 Wen-Chiuan Tsai [75]
Regulation of tumor cell metastasis Human Specimens, PDAC mice model 2014 Ang Li [76]
Regulation of tumor cell metastasis Human Specimens, Cell lines (MiaPaCa-2, Aspc-1) 2014 Xiao Zhao [77]
Diagnosis biomarker Human Specimens 2020 Magdalena Misiura [78]
Skin neoplasia FSCN1 Diagnosis biomarker Human Specimens 2002 Viktor N Goncharuk [79]
Lung cancer FSCN1 Diagnosis biomarker Human Specimens 2003 G Pelosi [80]
Diagnosis biomarker Human Specimens 2013 Yu Teng [81]
Diagnosis biomarker Human Specimens 2015 Xiao-Ling Ling [82]
Diagnosis biomarker Human Specimens 2015 Aihua Luo [83]
Diagnosis biomarker Human Specimens 2015 Wei Zhao [84]
Regulation of tumor cell growth and motility Cell lines (A549, SPC-A-1) 2016 Zhigang Liang [85]
Diagnosis biomarker Human Specimens 2016 Juanjuan Zhang [86]
Diagnosis biomarker Human Specimens 2017 L Yang [87]
Regulation of tumor cell motility Cell lines (A549, H520) 2018 Da Zhao [88]
Diagnosis biomarker Human Specimens 2018 Yunxia Zhang [89]
Regulation of tumor cell metastasis and recurrence Human Specimens, Cell lines (H1650, H23, H292, LLC)
mice animal model		 2019 Shengchen Lin [90]
Diagnosis biomarker Human Specimens 2020 E S Kolegova [91]
Regulation of tumor cell metastasis Human Specimens, Cell lines (H1650, A549, H292, H23, LLC) 2021 Shengchen Lin [92]
Cholangiocarcinoma FSCN1 Diagnosis biomarker Human Specimens 2004 Sharon L Swierczynski [73]
Diagnosis biomarker Human Specimens 2007 Kohji Okada [93]
Diagnosis biomarker Human Specimens 2009 Young Hoon Roh [94]
Diagnosis biomarker Human Specimens 2009 Kyu Yeoun Won [95]
Gastric cancer FSCN1 Diagnosis biomarker Human Specimens 2004 Yosuke Hashimoto [96]
Diagnosis biomarker Human Specimens 2007 Wen-Chiuan Tsai [97]
Regulation of tumor cell motility Human Specimens, Cell lines (MKN-28) 2010 Seok-Jun Kim [98]
Diagnosis biomarker Human Specimens 2013 Hidetaka Yamamoto [99]
Diagnosis biomarker Human Specimens 2012 Su Jin Kim [100]
Regulation of tumor cell motility Cell lines (GES-1, MKN45, MKN28, BGC823, AGS and SGC7901) 2014 Jun Yao [101]
Regulation of tumor cell growth and motility (HGC-27, MGC-803, MKN-25 and SGC-7901 2014 Lihua Guo [102]
Regulation of tumor cell motility AGS, MNK-45) 2015 Yunshan Yang [103]
Diagnosis biomarker In-silico analysis 2017 Hua-Chuan Zheng [104]
Diagnosis biomarker Human Specimens 2018 Byoung Kwan Son [105]
Esophageal Cancer FSCN1 Diagnosis biomarker Human Specimens, Cell lines (EC109, EC18, EC171, EC8712 and SHEEC) 2006 H Zhang [106]
Diagnosis biomarker Human Specimens 2010 Li-yan Xue [107]
Diagnosis biomarker Human Specimens 2017 Wen-Xia Chen [108]
Regulation of tumor cell growth and motility Cell lines (KYSE150, KYSE180) 2017 Fa-Min Zeng [109]
Kidney cancer FSCN1 Diagnosis biomarker Human Specimens 2006 Richard Zigeuner [110]
Adrenocortical carcinoma FSCN1 Diagnosis biomarker Human Specimens 2015 Giada Poli [111]
Regulation of tumor cell growth and motility Human Specimens, Cell lines (H295R) 2019 Giada Poli [112]
Colon cancer FSCN1 Diagnosis biomarker Human Specimens 2006 Yosuke Hashimoto [113]
Regulation of tumor cell motility Human Specimens, Cell lines (HT29, SW480, HCT116, CT26) 2007 Danijela Vignjevic [114]
Regulation of tumor cell motility Cell lines (SW480, SW1222, and DLD-1), subcutaneous xenograft model 2007 Yosuke Hashimoto [115]
Diagnosis biomarker Human Specimens 2010 Charles Chan [116]
Diagnosis biomarker Human Specimens 2012 Seung Yeop Oh [117]
Diagnosis biomarker Human Specimens 2011 Eun-Joo Jung [118]
Diagnosis biomarker Human Specimens 2013 Pablo Conesa-Zamora [119]
Regulation of tumor growth and metastasis Cell lines (SW480, HT29, LS174T, SW620, and LoVo) 2014 Y Feng [120]
Regulation of tumor cell growth and motility Transgenic mice 2014 Marie Schoumacher [121]
Diagnosis biomarker Human Specimens 2015 Josephine C Adams [122]
Diagnosis biomarker Human Specimens 2018 Barbara M Piskor [123]
Diagnosis biomarker Human Specimens 2020 Chao-Qun Wang [124]
Diagnosis biomarker In-silico analysis 2020 Shuai Shi [125]
Diagnosis biomarker Human Specimens 2021 Athanasios Tampakis [126]
Prostate cancer FSCN1 Regulation of tumor cell motility Human Specimens, Cell lines (DU145),
Orthotopic prostate xenograft models		 2009 Andrew D Darnel [127]
Diagnosis biomarker Human Specimens 2014 Daniel C Dim [128]
Diagnosis biomarker Human Specimens 2017 Matthew T Jefferies [129]
Oral cancer FSCN1 Regulation of tumor cell motility Cell lines (OECM-1, SCC-25) 2009 Su-Feng Chen [130]
proteases activity and tumor cell motility Cell lines (YD-10B, HSC-2, HSC-3, Ca9.22 OSCC) 2018 Min Kyeong Lee [131]
Melanoma FSCN1 Regulation of tumor cell motility Cell lines (A375MM, CHL-1, WM266.4, MV3) 2010 Ang Li [132]
Regulation of tumor cell growth and motility Fascin1 -/- mice 2013 Yafeng Ma [133]
Regulation of tumor angiogenesis Cell lines (B16F0) 2013 Yafeng Ma [134]
Stemness activity Cell lines (WM793, WM39) 2018 Jiaxin Kang [135]
Regulation of tumor cell growth Cell lines (WM793), subcutaneous xenograft model 2021 Byung-Soo Kang [136]
FSCN family Diagnosis biomarker In-silico analysis 2021 Cong Deng [44]
Bladder cancer FSCN1 Regulation of tumor cell viability and motility Human Specimens, Cell lines (BOY, T24m KK47) 2010 T Chiyomaru [137]
Diagnosis biomarker Human Specimens 2013 Mohamed Abd El-Rehim [138]
Lymphoma FSCN1 Diagnosis biomarker Human Peripheral blood mononuclear cells 2011 Andrea K Kress [139]
Regulation of tumor cell motility Cell lines (LCL-B, LCL-721, LCLs LCL-3 and LCL-4) 2014 Caroline F Mohr [140]
Leukemia FSCN1 Diagnosis biomarker Human Specimens 2018 Nabila El Kramani [141]
Liver cancer FSCN1 Regulation of tumor cell viability and motility Human Specimens, Cell lines (HLE, Hep3B, Huh7) 2011 Yoshihiro Hayashi [142]
Diagnosis biomarker Human Specimens 2011 Chih-Kung Lin [143]
Diagnosis biomarker Human Specimens 2012 Xiaodan Huang [144]
Chemoresistant Cell lines (SNU387, Huh7, Hep3B, and SNU449) 2018 Yuanbiao Zhang [145]
Endometrioid carcinoma FSCN1 Diagnosis biomarker Human Specimens 2012 Banu Dogan Gun [146]
Head and neck cancers FSCN1 Diagnosis biomarker Human Specimens 2014 Konstantinos Papaspyrou [147]
Diagnosis biomarker Human Specimens, Cell lines (OECM1, SAS, CGC8, and CGC9) 2015 Li-Yu Lee [148]
Brain cancer FSCN1 Regulation of tumor cell motility Cell lines (U251) 2015 Neil T Hoa [149]
Cervical cancer FSCN1 Regulation of tumor growth CaSki, subcutaneous xenograft model 2018 Xian Li [150]
Diagnosis biomarker Human Specimens 2018 Zohreh Yousefi Ghalejoogh [151]
Cardia cancer FSCN1 Diagnosis biomarker Human Specimens 2019 Li Wei [152]
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As a well-known molecule, Fascin-1 can be used as a diagnostic marker and is essential for cell growth and motility in multiple cancer types. The table lists the Fascin-1-related studies from 2000 to 2021, including the biological relevance of cancer types, validated with human tissues or tumor cell lines, and established in which tumor cell model.

1.5. Transactivation factors of Fascin-1

Stimulation by external factors, including physical or molecular factors, can trigger signal transduction to transactivate Fascin-1 expression. Currently, multiple upstream regulators have been identified to modulate the expression of Fascin-1 by interacting with the promoter region (Fig. 4).

Fig. 4.

Fig. 4

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The expression of Fascin-1 is regulated by diverse molecular pathways.

Inflammation-related factors, such as IL-1B, can induce Fascin-1 expression by the ERK/JNK/NF-κB/CREB cascade to promote oral squamous cell invasion, which can be reversed by treating cells with an antagonist of IL-1B [153]. Additionally, the evidence demonstrated that stimulation with IL-6 or TNF-α and Fas can induce STAT3-mediated Fascin-1 [56,101,103,154], in which the interaction of NF-κB and STAT3 may be required for binding to the Fascin-1 promoter. Similar to the response to viral infection and inflammatory situations, Fascin-1 can be found to be correlated with virus-related cancer progression.

Growth factors, such as EGF, have been found to induce the triple-negative breast cancer epithelial-to-mesenchymal (EMT) transition via MAPK/Fascin-1 [155]. As a downstream molecule of receptor tyrosine kinases, Tiam1 can regulate actin remodeling by targeting Fascin-1 [156]. Similar observations were described by Jeong et al., who found that Rab25 can activate EGFR/VEGF-A signaling by crosstalk; the integrin B1 receptor drives Snail to transactivate Fascin-1 expression, consequently promoting ovarian cancer malignancy [157]. In agreement with other reports, they demonstrated that ribosomal S6 kinase inhibitors can suppress Fascin-1 by blocking the RSK2-CREB axis [158]. Interestingly, the NF-κB consensus sequence shared a similar binding site for TCF/LEF. The report by Grothey et al. demonstrated that the ErbB2/HER2 tyrosine kinase receptor could stimulate the actin protrusion structure through the TCF/LEF motif to regulate breast cancer migration [46]. The TCF/LEF binding site is well known for the Wnt signaling cascade and can be activated with abnormal β-catenin.

For embryogenesis factors, related stimulation factors, such as TGF-β, were found to modulate the Fascin-1 level to control cell motility [159]. In addition, cell–cell interactions may trigger a similar phenomenon. According to a report by Qian, Notch4-mediated Fascin-1 contributes to cell motility in pancreatic cancer [160]. In agreement with other reports, extracellular factors, such as EGF and TGF-β, can transactivate Fascin-1 via the MER-REK-SP1 and Smad4 cascades [161]. Interestingly, Sun et al. found that TGF-β-induced Fascin-1 can be negatively regulated by the EMT-related factor GATA3 [162]. Similar observations were described for the Wnt/TGF-β downstream factor Myc. Myc can crosstalk with Rho signaling to serve as an essential transcription factor binding to the Fascin-1 promoter to promote filopodia formation [163].

The molecular network involved in Fascin-1 transactivation-related events, including extracellular stimulators, signaling pathways, and upstream regulators, was organized based on its current identification in cancer.

1.6. Downstream effectors of Fascin-1

1.6.1. Downstream effectors

1.6.1.1. MMP

In addition to being transactivated by various stimulators, Fascin-1 is capable of regulating filopodia morphology by downstream effectors. A filopodia morphology can be easily observed when cells migrate, in which Fascin-1-mediated molecular regulation is needed. Currently, Fascin-1 has been identified as binding F-actin and diverse molecules to mediate filopodia formation. Additionally, molecular interactions can trigger signal transduction. Notably, Fascin-1-mediated cell motility can be regulated by posttranslational modifications (Fig. 5). It was found that in shRNA-based knockdown of Fascin-1 cells, multiple protease-related enzymes were decreased, including matrix metalloproteinase (MMP) and cysteine cathepsins [131]. Similar observations were described by Al-Alwan et al., who reported that Fascin-1 could regulate NF-κB and urokinase-type plasminogen activator as well as MMPs in breast cancer. In agreement with other reports demonstrating that invasiveness was correlated with Fascin-1 expression, one study showed that downregulation of Fascin-1 can decrease the EMT-related factors SNAI1/2 and MMPs and thus activate E-cadherin expression to suppress EMT [142].

Fig. 5.

Fig. 5

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Fascin-1-mediated molecular regulation contributed to filopodia morphology.

The related postmodification regulators of Fascin-1 and downstream effectors or interaction partners of Fascin-1 were organized. The simulated crystal structure (ID:1DFC) was generated from NCBI websites.

1.6.1.2. BRMS1

Notably, overexpression of Fascin-1 can abrogate the level of tumor suppressor breast cancer metastasis suppressor-1 (BRMS1) in the nucleus [164]. However, evidence suggests that BRMS1 can negatively regulate Fascin-1 as well, consequently suppressing metastasis ability [165].

1.6.1.3. Hippo-MAPK axis

Additionally, some studies have found that Fascin-1 regulates the Hippo and MAPK pathways to alter cell malignancy [88,166].

1.7. Protein–protein interaction

In general, Fascin-1 mediates filopodia by interacting with actin to contribute to cell motility. Therefore, the biological functions of Fascin-1 may depend on its protein–protein interaction partner. In cancer, the dynamic between Fascin-1 and F-actin interaction was observed, and Pfisterer et al. demonstrated that FMNL2 and Fascin-1 interaction could accelerate binding to F-actin and was essential to filopodia structure stabilization [167]. In addition, Fascin-1 interaction with the FH domain of Daam1 was required for filopodia formation in breast cancer [168]. In lung cancer, Fascin-1 has been shown to dominate the YAP/TEAD axis by interacting with MST1 to promote invasive cells [85]. Similar processes can be found in esophageal squamous cell carcinoma. The interaction complex between Fascin-1/LOXL2/EZR/HSPB1/TMOD3 contributes to cell cytoskeleton reconstruction during migration [169].

1.8. Posttranslational modification of Fascin-1

In addition to being transactivated by various stimulators, Fascin-1 is capable of regulating filopodia morphology by downstream effectors. A filopodia morphology can be easily observed when cells migrate, in which Fascin-1-mediated molecular regulation is needed. Currently, Fascin-1 has been identified as binding F-actin and diverse molecules to mediate filopodia formation. Additionally, molecular interactions can trigger signal transduction. Notably, Fascin-1-mediated cell motility can be regulated by posttranslational modifications (Fig. 5). Modifications of proteins can alter their structure to affect their stability and interaction ability. These modification processes can occur in Fascin-1, especially phosphorylation. Thus far, four phosphorylation sites have been identified in Fascin-1, including tyrosine 23, threonine 403 [170] and serine 38/39/274 [109]. A Fascin's ability to bundle actin is determined by its state of dephosphorylation [171]. For example, phosphorylation at serine 39 on Fascin-1 by protein kinase C (PKC) can deactivate its bundling activity to F-actin [172]. During the progression of esophageal cancer, Facin-mediated cell motility can be regulated by phosphorylation of threonine 403 by AKT2 [170]. On the other hand, studies demonstrated that serine to alanine substitution (S39A) of Fascin-1 could mimic dephosphorylation status [173]. Interestingly, such processes can be regulated by diverse molecules and contribute to cancer progression. Evidence demonstrated that nonphosphorylated Fascin-1 could bind to FMNL2, which accelerated the movement of Fascin-1 into filopodia from lamellipodia. In turn, FMNL2 can modulate the proportion of Fascin-1 between filopodia and lamellipodia [167]. Similar results can be observed in Zeng et al., who identified that the migration ability of esophageal squamous cancer cells could be regulated by the dephosphorylation of Fascin-1 in β-trefoil domain 1 (Tyrosine 23, Serine 38/39) and β-trefoil domain 3 (Serine 274) [109]. Studies have recently revealed that the acetylation of Fascin performs a similar function to phosphorylation. It has been reported that the acetyltransferase P300/CBP-associated factor (PCAF) can regulate esophageal tumor cell metastasis through acetylation of Fascin-1 at lysine 471 [174]. Additionally, Smurf1-mediated monoubiquitination of lysine 247/250 on Fascin-1 contributed to the interaction with F-actin but not protein stability; lysine to arginine substitution (K247R/K250R) of Fascin-1 can trigger the migration ability of colon cancer [175]. Therefore, various modification sites have been identified in Fascin-1, which may participate in protein stability and activity.

2. Noncanonical functions of Fascin-1 in cancer

It has been postulated that the molecular regulation of cell motility by Fascin may be divided into two types: those that are dependent on F-actin binding proteins and those that are independent. Many researchers have recently identified such independent actin-binding functions as noncanonical functions of Fascin [92,[176], [177], [178], [179], [180]]. Notably, Fascin-mediated EMT contributed to reprogramming events and was linked to clinical treatment issues. Fascin-1-independent F-actin binding biological functions have been identified to contribute to cancer progression, including metabolism reprogramming, chemotherapy resistance, and stemness activity. Significantly, such processes reprogram the tumor microenvironment and accelerate tumor aggressiveness (Fig. 6). The focus of this section was on the role of Fascin in promoting cancer progression through non-F-actin-binding events.

Fig. 6.

Fig. 6

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Noncanonical biological functions of Fascin-1 in cancer.

The F-actin-independent molecular regulation network of Fascin-1 was organized according to related events of metabolic reprogramming, chemoresistance, stemness activity, and the tumor microenvironment.

2.1. Metabolism

Dysregulation of metabolism, including carbohydrates, lipids, and proteins, has contributed to cancer progression. Interestingly, cell motility can be affected by vitamin metabolism processes. For example, the All-trans-Retinoic acid metabolic-related enzyme CYP26A1 has been identified as being associated with cancer progression. An omics-based comparative analysis showed that Fascin-1 was upregulated in CYP26A1-overexpressing cells. Conversely, downregulation of Fascin-1 can abrogate cell growth and motility and subsequently induce apoptosis and senescence [181]. A similar approach can be observed in Lin et al.; metabolomics and proteomics-based analysis identified Fascin-1 links to the mitochondrial oxidative phosphorylation system by modulating mitochondrial Complex I and mitochondrial actin filaments [90], therefore demonstrating that Fascin-1 can regulate carbohydrate metabolism events to dominate the cell phenotype. However, as a mesenchymal-epithelial negative regulator, inositol has been reported to downregulate Fascin-1 expression via the PI3K/AKT axis, which suppresses breast cancer aggressiveness [182]. Furthermore, a similar proteomics-based approach identified that fatty acid synthase can bind to Fascin-1 directly to control the EMT phenotype of cells [183]. Such processes can be observed in breast cancer. Cells express more Fascin-1 via linoleic acid to promote cell migration and invasion [184]. This finding demonstrates that fatty acid metabolism-mediated Fascin-1 is a risk factor for cancer progression. In addition, dysregulation of amino acid metabolism has been found to be linked to cancer malignancy. Growing evidence shows that the expression of leucine aminopeptidase 3 is associated with cancer progression. The expression of leucine aminopeptidase 3 can regulate breast cancer cell motility via Fascin-1 [185]. Similar results can be observed in Fang et al., in which knockdown of leucine aminopeptidase 3 decreased Fascin-1 expression in ovarian cancer as well as cell migration ability [186].

2.2. Chemotherapy-resistance

Drug resistance enables cancer cells to survive treatment. Studies have shown that TS-1, as a standard treatment for oral and pancreatic cancer, induces resistance, and proteomics-based analysis revealed that Fascin-1 was upregulated in TS-1-resistant pancreatic cancer cells [187]. Treating cells with doxorubicin upregulated Fascin-1 expression in human KB carcinoma [188]. Mechanistically, the Fascin-derived PI3K/AKT axis can resist doxorubicin-induced apoptosis and is correlated with poor prognosis of breast cancer outcomes [189]. Growing evidence shows that various factors that can induce drug resistance require Fascin-1 expression. A roline to histidine substitution (P64H) of galectin-3 can promote nuclearization and accelerate the interaction with β-catenin to transactivate Fascin-1 [190]. Additional related stimulation factors can be observed in gastric and pancreatic cancer. Studies have found that knockdown of zinc finger protein 139 can downregulate Fascin-1 to induce drug sensitivity [191]. In pancreatic cancer, the expression of Notch4 was correlated with docetaxel resistance; knockdown of Notch4 can suppress Fascin-1 via the AKT/GSK3β axis to enhance cell sensitivity, consequently suppressing tumor cell drug resistance and motility [192].

2.3. Stemness activity

Self-renewal and embryonic features that characterize cell pluripotency are defined as “stemness” activity. In cancer, stemness may be contributed to by EMT processes, in which cells have more mesenchymal and stem-like marker expression as well as drug-resistant ability. According to a report by Barnawi et al., overexpression of Fascin-1 can induce stem-like markers and sphere formation via integrin-β1; coexpression of Fascin-1 and integrin-β1 provides a worse prognosis for breast cancer [193]. Under chronic inflammatory conditions, colonic polyp-derived differentiated adenomatous polyposis cells have been identified with an anchorage-independent growth phenotype and stemness-related marker expression, including CD44, CD166, and LGR5. Mechanistically, related chronic inflammatory factors, such as TNF-α- and IL-1β-mediated miR-146a expression, can increase Fascin-1 stability to promote stemness activity [194]. The same effect was observed by Barnawi and coworkers, who showed that the expression of Fascin-1 was correlated with the expression of EMT and stemness markers and that knockdown of Fascin-1 decreased tumorsphere formation and increased the sensitivity to doxorubicin [195]. In melanoma, knockout of Fascin-1 can reduce stemness characteristics. Interestingly, the Fascin-1 and MST2 interaction drives nonactin binding functions to increase Hippo pathway-related factor TAZ stability; consequently, there is dominant tumor cell sphere formation [196].

2.4. Immune evasion in the tumor microenvironment

Human T-cell leukemia virus type 1 was demonstrated to induce lymphoma by transfecting T cells, in which Fascin-1 serves as a downstream effector of the viral-related protein Tax and is transactivated by NF-кB [197]. In addition, staining Fascin-1 for circulating myeloid dendritic cells can be used as a specific indicator for diagnosis in pancreatic cancer [198]. In follicular lymphomas, the level of Fascin-1 in germinal center dendritic cells was decreased, which may explain why the tumor microenvironment can change the activity of germinal center dendritic cells to reduce antigen presentation into T cells to modulate the immune response [199]. Similar observations were described in Fascin-1/CXCL9-positive dendritic cells, where they are involved in stromal cells and can interact with T cells to modulate immune stimulation in gastric cancer [200]. A mouse model revealed that Fascin levels are related to conventional dendritic cell activity, and inhibition of Fascin can effectively expose tumor antigens to conventional dendritic cells and increase CD8+ T cells' antitumor immune responses [201].

This finding was in agreement with the fact that Fascin-1 can be linked to the tumor immune microenvironment. In addition, studies recently showed that cancer-associated fibroblasts could trigger cancer cells expressing Fascin-1 via TGF‑β1, EGF, or IL‑1β-mediated RhoA and NF-кB signaling [202] and may serve as a biomarker for cancer-associated fibroblasts [203]. Similarly, this effect can be observed in McGuire et al., who identified that Fascin-1 is expressed in both ovarian cancer and stromal cells, and downregulated Fascin-1 can abrogate tumor metastasis activity [70]. Additionally, Fascin-1 has been detected in serum, and the level of Fascin-1 can be used as a marker in lung cancer [204]. A similar approach was described in Chen et al., who revealed that the developed Fascin-1 autoantibodies could be used to distinguish the stage of esophageal squamous cell carcinoma [205]. Recently, extracellular vesicles have been considered critical mediators for tumor cells communicating with the microenvironment [206]. Thus, Fascin-1 can participate in the delivery of extracellular vesicles to promote cancer invasiveness [207]. In addition, the tumor microenvironment is considered to have more hypoxic conditions. Under this circumstance, HIF-1α was identified as a transcription factor and can bind to the Fascin-1 promoter to transactivate directly, consequently regulating cell motility [208]. Mechanistically, Fascin-1-mediated invasiveness with MMP [131] and filopodia morphology may contribute to angiogenesis [209]. In particular, Fascin-1 has been identified to participate in tumor self-seeding, which promotes tumor extravasation and related events [210].

3. Available inhibitors for Fascin-1

Currently, available inhibitors have been designed to target Fascin-1 and applied in cancer therapy. This section lists current strategies for targeting Fascin-1. Fascin-1 must be considered a critical target for cancer therapy. Therefore, multiple specific compounds have been designed to block Fascin-1 by directly interacting with its actin-binding sites. Interestingly, posttranslational modification can also change Fascin-1 activity. In addition, the evidence demonstrated that targeting upstream regulators of Fascin-1 may provide an alternative way to block Fascin-1-mediated cancer progression (Fig. 7).

Fig.7.

Fig.7

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The available targeting strategies for Fascin-1.

Direct and indirect inhibitors of Fascin-1 are listed according to the current treatment in cancer.

3.1. Specific inhibitors

3.1.1. Macroketone

Fascin-1 is well known for its actin-binding ability. Therefore, targeting Fascin-1 by blocking its actin-binding sites would be efficient. Based on the crystal structure and molecular docking simulation analysis, macroketone can bind to Fascin-1 and shade actin-binding sites. Significantly, the glutamate to alanine substitution (E391A) or histidine to alanine substitution (H474A) of Fascin-1 can block macroketone binding. Interestingly, studies demonstrated that the H474A mutation could resist macroketone treatment and accelerate cell invasive activity [211].

3.1.2. N-(1-(4-(Trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide derivative compound

Huang and coworkers showed as an imaging-based assay that high throughput identification identified N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide, also called Fascin-1 inhibitor G2, can bind to Serine 39 on Fascin-1 directly. The serine to aspartate substitution (S39D) of Fascin-1 can block Fascin-1 inhibitor G2 binding, in which the binding between Fascin-1 inhibitor G2 and Fascin-1 can modulate serum-stimulated filopodia morphology to block breast cancer metastasis [212]. This finding was in agreement with that previously reported by McGuire et al., who demonstrated that targeting Fascin-1 with the Fascin-1 inhibitor G2 in both ovarian cancer and cancer-associated fibroblasts can suppress metastasis [213]. A similar observation was described in colorectal cancer. Treating cells with the Fascin-1 inhibitor G2 can suppress cell migration and invasion activity [214]. Furthermore, to improve the efficiency of the Fascin-1 inhibitor G2, related derivatives, including NP-G2-011 and NP-G2-044, were developed to inhibit metastasis. Notably, in contrast to the G2 binding site of Fascin-1 inhibitors, NP-G2-044 was designed to target Fascin-1 by binding glutamate 391 to prevent actin bundling [215]. In particular, NP-G2-044 seems specific to activated B-cell subtype lymphoma. Mechanistically, targeting Fascin-1 with NP-G2-044 can modulate ERK/PLCγ1/PI3K/p65 to prevent metastasis [216]. Notably, recent studies have shown that NP-G2-044 can improve the survival rate and reactivate the immune response by modulating the Fascin-1 level in dendritic cells, and the antitumor ability has been evaluated by clinical trials (NCT05023486, NCT03199586) [201]. Similar to the Fascin-1 inhibitor G2-based derivatives, NP-G2-029 and its binding affinity can be changed by isoleucine to alanine substitution (I39A) and phenylalanine to alanine substitution (F216A). In contrast to NP-G2-044, NP-G2-029 had a low IC50 against diverse mutations of Fascin-1, including F14A, W101A, F14A/W101A, I93A, F216A, and I93A/F216A [217].

3.1.3. Thiazole derivative compound

A series of thiazole derivative compounds have been designed to target Fascin-1, in which the thiazole Compounds 5o and 5p showed powerful inhibition of cell motility and angiogenesis [218].

3.1.4. Others

Tetrahydropyrimidine derivatives have been designed to inhibit Fascin-1. Significantly, Compounds 3a and 4e can suppress Fascin-1-mediated cell motility [219]. Similar studies were reported by Francis et al., who designed a Fascin-1-specific inhibitor by modulating the structure of N-phenylacetamide with benzyl substituents and identified BDP-13176. Currently, BDP-13176 is used as an abatable commodity for targeting Fascin-1 [220]. Notably, the antiviral raltegravir [221] and the antidepressant imipramine [222], used for repurposing, effectively inhibited colorectal cancer metastasis in vitro and in vivo by binding to Fascin. In particular, Raltegravir has a similar binding site to NP-G2-029, but it may be more stable [221].

3.2. Indirect targeting

Currently, targeting upstream regulators of Fascin-1 can modulate the related expression and abrogate Fascin-1-mediated biological functions. Therefore, indirect targeting strategies were organized.

3.2.1. Natural products

Herbal medicines are considered to come from natural products and cause mild side effects in cells. Studies have demonstrated that the extract from Elaeagnus angustifolia has anticancer activity. Treating cells with Elaeagnus angustifolia extract can decrease Fascin-1 expression and downregulate the ErbB2/JNK/Jun/β-catenin axis as well as EMT-related markers to induce cell apoptosis, consequently abrogating Her2-positive breast cancer progression [223]. Another natural product, chalcones and their derivatives, has been identified to modulate the expression of Fascin-1 in KRAS-mutated colorectal cancers [214]. Similar effects can be observed with the herbal compound curcumin. STAT3 has been described as an upstream regulator of Fascin-1 [56,101,103,154], and curcumin can target the JAK/STAT3 axis to modulate Fascin-1 in ovarian cancer [224]. Extracts such as crispene E and ilamycin C were reported to downregulate Fascin-1 by abrogating STAT3 dimerization in breast cancer [225,226]. Therefore, targeting the upstream regulator of Fascin-1 may provide an alternative strategy.

3.2.2. Synthetic compound

The IKKβ inhibitor ACHP can suppress NF-κB-mediated Fascin-1 [227], sevoflurane can inhibit HIF-1α-mediated Fascin-1 [228], polyisoprenylated cysteinyl amide or salinomycin can block RhoA-mediated Fascin-1 [229,230], and FMK-MEA can abrogate RSK2/CREB-mediated Fascin-1 [231]. Meanwhile, the leucine aminopeptidase 3 inhibitor bestatin has been identified with identical effects [232]. In addition, the effects of thiazole derivatives have been described [218]. Zheng et al. identified that compound-5k could modulate Fascin-mediated filopodia morphology to control cell growth and motility [233]. The synthetic compound PQ401 was designed for IGF-1 receptor inhibition. Treating cells with PQ401 can suppress IGF-1-mediated Fascin-1 in skin cancer [234]. Notably, 12-O-tetradecanoylphorbol-13-acetate has been reported to phosphorylate Fascin-1 to inactivate its activity [235]. However, the controversial effects of 12-O-tetradecanoylphorbol-13-acetate have been described, which can induce the PKC/STAT3/β-catenin/Fascin-1 axis to promote breast cancer cell motility [236] and act as an anticancer reagent by suppressing YAP/AMOT in hepatocellular carcinoma [237].

3.2.3. Recombinant peptide

A similar process can be observed in recombinant porcine natural killer lysine, which was derived from porcine intestinal tissue. When receiving this peptide, Fascin-mediated β-catenin, as well as MMP2/9, were decreased, thus inhibiting hepatocellular carcinoma cell adhesion and migration ability [238]. Additionally, targeting metabolism-related events has been considered to efficiently block nutrient uptake to cancer. Treatment of cells with all-trans-retinoic acid can decrease CYP26A1-mediated Fascin expression, thus attenuating breast cancer aggressiveness [181].

3.2.4. Hormones

Melatonin is a hormone and can be generated from the human brain. Growing evidence has demonstrated that melatonin has anticancer activity. Studies have reported that supplements with melatonin suppress nicotine-mediated Fascin-1 in breast cancer [239].

4. Conclusion

The biological functions of Fascin are linked to embryogenesis and carcinogenesis. It has been suggested that dysregulated cells might reactivate their expression to enhance cancer progression, especially for Fascin-1. This review systematically discusses the biological functions of Fascin-1 and its application value as a molecular target in tumor therapy. Notably, the noncanonical functions of Fascin may be distributed by specific conditions, subcellular locations, and interacting partners. With the leap forward to a single-cell level analysis, the roles of Fascin in the microenvironment will be unveiled. Most research focuses on fascin-1, and very little is known about fascin-2 and fascin-3, which can be explained by the distribution of expression in somatic cells. However, evidence indicates that they share similar functions and may compensate for each other. Recently, there is preliminary evidence highlighting the co-expression of Fascin-1 and Fascin-2 that has been found to be useful for diagnosing cancer patients [44] and may contribute to the regulation of novel non-coding RNAs [240]. Noteworthy, it has been found that metals–organic frameworks can affect mitotic processes by targeting F-actin-related molecules such as Fascin-2, thus causing cytotoxicity in tumor cells [241]. Evidence from these studies gradually supports the notion that Fascin-2 can be a potent target for improving the progression of cancer. Therefore, a comprehensive molecular characterization of Fascin-1, Fascin-2 and Fascin-3 might provide an alternative treatment strategy that targets the Fascin family more specifically.

Resource

Funding

None.

CRediT authorship contribution statement

Chien-Hsiu Li: Writing – original draft, Resources, Software, Writing – review & editing. Ming-Hsien Chan: Data curation, Writing – review & editing. Shu-Mei Liang: Data curation. Yu-Chan Chang: Writing – review & editing, Supervision. Michael Hsiao: Writing – review & editing, Supervision.

Declaration of Competing Interest

None.

Acknowledgments

This review study was supported by the Genomics Research Center of Academia Sinica, Taiwan to Michael Hsiao.

Contributor Information

Yu-Chan Chang, Email: jameskobe0@gmail.com.

Michael Hsiao, Email: mhsiao@gate.sinica.edu.tw.

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