Fascin regulates chronic inflammation‐related human colon carcinogenesis by inhibiting cell anoikis

Kanda, Yusuke; Kawaguchi, Tokuichi; Kuramitsu, Yasuhiro; Kitagawa, Takao; Kobayashi, Taiyo; Takahashi, Norihiko; Tazawa, Hiroshi; Habelhah, Hasem; Hamada, Jun Ichi; Kobayashi, Masanobu; H, Mio; Onuma, Kunishige; Osaki, Mitsuhiko; Nakamura, Kazuyuki; Kitagawa, Tomoyuki; Hosokawa, Masuo; Okada, Futoshi

doi:10.1002/pmic.201300414

Cited by 25 publications

(21 citation statements)

References 35 publications

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“…The overexpression of fascin has been reported in almost all the carcinomas (2,14,26,27), and fascin overexpression uniformly correlates with aggressive clinical course, metastatic progression, and poor prognosis (14, 28 -33). The transcriptional regulation of fascin in cancer has been extensively studied, with inflammatory cytokines, hypoxia, epithelial to mesenchymal transcription factors, and Wnt/␤-catenin pathways, among others, being implicated in the up-regulation of fascin levels in various cancers (33)(34)(35)(36)(37)(38). In contrast, little is known about the post-translational regulation of fascin other than the Ser 39 phosphorylation by PKC.…”

Section: Discussionmentioning

confidence: 99%

Monoubiquitination Inhibits the Actin Bundling Activity of Fascin

Lin¹,

Lü²,

Mulaj³

et al. 2016

Journal of Biological Chemistry

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Edited by Velia M. FowlerFascin is an actin bundling protein that cross-links individual actin filaments into straight, compact, and stiff bundles, which are crucial for the formation of filopodia, stereocillia, and other finger-like membrane protrusions. The dysregulation of fascin has been implicated in cancer metastasis, hearing loss, and blindness. Here we identified monoubiquitination as a novel mechanism that regulates fascin bundling activity and dynamics. The monoubiquitination sites were identified to be Lys 247 and Lys 250 , two residues located in a positive charge patch at the actin binding site 2 of fascin. Using a chemical ubiquitination method, we synthesized chemically monoubiquitinated fascin and determined the effects of monoubiquitination on fascin bundling activity and dynamics. Our data demonstrated that monoubiquitination decreased the fascin bundling EC 50 , delayed the initiation of bundle assembly, and accelerated the disassembly of existing bundles. By analyzing the electrostatic properties on the solvent-accessible surface of fascin, we proposed that monoubiquitination introduced steric hindrance to interfere with the interaction between actin filaments and the positively charged patch at actin binding site 2. We also identified Smurf1 as a E3 ligase regulating the monoubiquitination of fascin. Our findings revealed a previously unidentified regulatory mechanism for fascin, which will have important implications for the understanding of actin bundle regulation under physiological and pathological conditions.The compact and straight actin bundles are critical for mammalian cells to generate finger-like protrusions such as filopodia and stereocillia. These protrusions are required for diverse physiological functions including cell motility, hearing, and nutrient absorption. Fascin is a monomeric actin bundling protein essential for maximal cross-linking of actin filaments into compact and rigid bundles (1). There are three fascin isoforms (fascin-1, -2, and -3) in metazoans, with fascin-1 expressed mostly in cells with neuronal and mesenchymal lineage, fascin-2 expressed in hair cells and photoreceptor cells, and fascin-3 expressed almost exclusively in the testis (1). The dysregulation of fascin proteins has been associated with various diseases. For example, fascin-1 (hereafter referred to as fascin) is overexpressed in almost all the carcinomas (2, 3). It is believed that fascin promotes cancer metastasis by facilitating the formation of filopodia and invadopodia, which promote cancer cell motility and invasiveness (2, 4). The expression of fascin-2 is limited to the inner ear and retina (1). The loss of function mutations of fascin-2 have been correlated with hearing loss and autosomal dominant retinitis pigmentosa, presumably because of defective actin bundle structures in hair cell stereocillia and photoreceptors (5-10). Understanding the molecular mechanisms underlying fascin bundling activity and its regulation may provide new avenues to prevent cancer metastasis and to treat pat...

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Section: Discussionmentioning

confidence: 99%

Monoubiquitination Inhibits the Actin Bundling Activity of Fascin

Lin¹,

Lü²,

Mulaj³

et al. 2016

Journal of Biological Chemistry

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“…Systems for coculture of tumor-derived cells with normal cells of the tumor microenvironment may improve understanding of environmental cues that activate fascin-1 expression in colonic adenomas. Investigation of the relationship between intestinal inflammation, fascin-1 and tumor progression in mice has begun [50]; more widespread investigations can be expected in the next 5 years. Fascin-1 is a driver of tumor 'self-seeding' (the expansion of a primary tumor through infiltration by tumor cells shed into the circulation) by metastatic breast cancer cells; it is of interest to discover if this process also applies to colorectal cancers [60].…”

Section: Five-year Viewmentioning

confidence: 99%

“…The possible role of inflammatory cues in driving the upstream pathways that activate fascin-1 transcription in colonic epithelial cells is also supported by data from a mouse xenograft model for inflammation-driven tumorigenesis. In this model, progression of human adenoma-derived cells to adenocarcinomas is driven by foreign body-induced inflammation and is accompanied by upregulation of fascin-1 and several other actin-binding proteins [50].…”

Section: Mortality Lymph Node Invasion Distant Metastasismentioning

confidence: 99%

Fascin-1 as a biomarker and prospective therapeutic target in colorectal cancer

Adams

2014

Expert Review of Molecular Diagnostics

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Fascin-1 is a filamentous actin-binding protein that crosslinks actin microfilaments into tight, parallel bundles. These bundles are important for the extension of microspikes, filopodia and invadopodia from cell surfaces and for the functionality of these protrusions in cell migration and/or dynamic sensing of the local microenvironment. Fascin-1 is absent in normal colonic epithelium, but its upregulation in colorectal adenomas and adenocarcinomas and its correlation with an aggressive clinical course has piqued the interest of many laboratories with research interests in cancer metastasis. This report summarizes current knowledge of the molecular interactions of fascin-1 in relation to its activities and mechanisms of upregulation in colorectal carcinoma cells. The status and key questions surrounding investigations of fascin-1 as a novel, early prognostic biomarker in colorectal cancer are discussed. Ongoing pre-clinical research into new migration inhibitory and anti-metastatic compounds that alter the actin cytoskeleton, and the goal of targeting fascin-1, is also discussed.

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“…The genome of mammals codes three isoforms of fascin: Fascin-1, which occurs physiologically in neurons, fibroblasts, endothelial cells, smooth muscles cells, dendrite and mesenchymal cells; Fascin-2 found in the retina cells and Fascin-3 occurring in the testis [6][7][8]. In normal epithelial cells, Fascin-1 is not expressed, whereas its overexpression is observed in the neoplastic cells, including CRC cells [7,[9][10][11]. Fascin-1 has two F-actin binding sites.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical expression of Fascin-1 in colorectal cancer in relation to clinical and pathological parameters

Piskór

Pryczynicz

Lubowicka

et al. 2018

Folia Histochem Cytobiol.

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Introduction. Fascins are a group of proteins taking part in the maintenance of a proper structure of the cellular cytoskeleton. Fascin-1 is an actin-bundling protein present in neurons, fibroblasts, endothelial, smooth muscle, dendritic and mesenchymal cells whereas lack of its expression is characteristic of epithelial cells. Fascin-1 overexpression can be observed in neoplastic cells. Therefore, the aim of this study was to assess the expression of Fascin-1 protein in patients with colorectal cancer (CRC) and to analyze associations between Fascin-1 expression and clinical-pathological parameters. Material and methods. The study material included postoperative samples (tumor and unchanged colon tissue) obtained from 51 CRC patients. Fascin-1 expression was assessed in the paraffin sections by immunohistochemistry. Results. A statistically significant correlation was found between the histological type of cancer and the expression of Fascin-1 (p = 0.012). Increased expression of Fascin-1 in CRC was more frequent in adenocarcinoma type without the mucosal component with a better prognosis and decreased expression of this protein correlated with infiltration of cancer cells to blood and lymphatic vessels (p = 0.038). Conclusions. Our findings indicate a potential role of Fascin-1 in the pathogenesis of colon cancer; however, further studies will show whether this protein plays a role in the infiltration of colorectal cancer cells.

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Fascin regulates chronic inflammation‐related human colon carcinogenesis by inhibiting cell anoikis

Cited by 25 publications

References 35 publications

Monoubiquitination Inhibits the Actin Bundling Activity of Fascin

Monoubiquitination Inhibits the Actin Bundling Activity of Fascin

Fascin-1 as a biomarker and prospective therapeutic target in colorectal cancer

Immunohistochemical expression of Fascin-1 in colorectal cancer in relation to clinical and pathological parameters

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