Fascin Is Regulated by Slug, Promotes Progression of Pancreatic Cancer in Mice, and Is Associated With Patient Outcomes

Li, Ang; Morton, Jennifer P.; Ma, Yafeng; Karim, Saadia A.; Zhou, Yan; Faller, William J.; Woodham, Emma F.; Morris, Hayley; Stevenson, Richard P.; Juin, Amélie; Jamieson, Nigel B.; Mackay, Colin; Carter, C. Ross; Leung, Hing Y.; Yamashiro, Shigeko; Blyth, Karen; Sansom, Owen J.; Machesky, Laura M.

doi:10.1053/j.gastro.2014.01.046

Cited by 105 publications

(130 citation statements)

References 44 publications

(55 reference statements)

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“…Associations of binding specificity of Slug with these Ebox elements of CDH1 and Slug promoters were also affirmed using qPCR ( Figure 5A,5B). Thus, cell-free EMSA as well as synthetic ChIP-PCR assays affirmed similar, specific interactions of Slug with E-boxes in the CDH1 and Slug promoters like other members of the Snail family [28][29][30][31][32][33], with Slug displaying a moderate to strong affinity for 5"-CACCTG-3", weak affinity for 5"-CAGGTG-3" and none for 5"-CAGCTG-3" sequences [34,35]. Taken together, these results suggest possible auto-regulation of Slug.…”

Section: Accepted Manuscriptmentioning

confidence: 63%

Auto-regulation of Slug mediates its activity during epithelial to mesenchymal transition

Kumar

Uppuladinne

Jani

et al. 2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Slug, a five C2H2 zinc finger (ZF) motif transcription factor mediates cell migration in development, adult tissue repair and regeneration, as well as during tumor metastases through epithelial to mesenchymal transition. At the molecular level, this involves interactions with E-box (CACC/GGTG) consensus elements within target gene promoters to achieve transcriptional repression. However, precise elucidation of events involved in this DNA recognition and binding of specific promoters to regulate target genes have not been achieved. In the present study, we show that besides transcriptional repression, Slug can also directly activate its own expression by preferential binding to specific E-box elements in the distal binding region of its promoter. Our findings suggest that while the first ZF does not contribute to the transcription-associated functions of Slug, all the remaining four ZFs are involved in regulating the expression of target genes with ZF3 and ZF4 being more crucial than ZF2 or ZF5. We also report that recognition and binding preferences of ZFs are defined through intrinsic differences in the E-box core base pairs and/or flanking sequences, with the S2 E-box element being most critical during autoregulation. However, specific target E-box recognition and binding are also defined by the cellular context, which implies that in silico and/or biochemical DNA binding preferences may not necessarily be able to accurately predict in situ events. Our studies thus constitute a novel understanding of transcriptional regulation.

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Section: Accepted Manuscriptmentioning

confidence: 63%

Auto-regulation of Slug mediates its activity during epithelial to mesenchymal transition

Kumar

Uppuladinne

Jani

et al. 2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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“…Li et al [24] showed Facin-1 presence of in 95% of pancreatic ductal adenocarcinoma cells. In this study, the high histoscore significantly correlated with a lower patients' survival rate, invasion to blood and lymphatic vessels and advanced staging of cancer.…”

Section: Discussionmentioning

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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“…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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Fascin Is Regulated by Slug, Promotes Progression of Pancreatic Cancer in Mice, and Is Associated With Patient Outcomes

Cited by 105 publications

References 44 publications

Auto-regulation of Slug mediates its activity during epithelial to mesenchymal transition

Auto-regulation of Slug mediates its activity during epithelial to mesenchymal transition

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

Monoubiquitination Inhibits the Actin Bundling Activity of Fascin

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