GATA3 Transcription Factor Abrogates Smad4 Transcription Factor-mediated Fascin Overexpression, Invadopodium Formation, and Breast Cancer Cell Invasion

Sun, Jianwei; He, Huifang; Pillai, Smitha; Xiong, Yin; Challa, Sridevi; Xu, Li‐Yan; Chellappan, Srikumar; Yang, Shung‐Haur

doi:10.1074/jbc.m113.506535

Cited by 48 publications

(44 citation statements)

References 44 publications

(57 reference statements)

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“…Our data further suggested that fascin overexpression increased MMP-2 expression through PKC-ERK signaling, which may at least partially account for the elevated invasiveness in fascin-overexpressing PDAC cells. It is also worth noting that fascin has been implicated in invadopodium formation in melanoma and breast cancer (39)(40)(41). It remains to be determined whether fascin-mediated invadopodia formation is involved in PDAC invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Inducible Factor-1 Promotes Pancreatic Ductal Adenocarcinoma Invasion and Metastasis by Activating Transcription of the Actin-Bundling Protein Fascin

et al. 2014

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Because of the early onset of local invasion and distant metastasis, pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor, with a 5-year survival rate of less than 5%. In this study, we investigated the role of fascin, a prometastasis actin-bundling protein, in PDAC progression, invasion, and the molecular mechanisms underlying fascin overexpression in PDAC. Our data showed that the expression levels of fascin were higher in cancer tissues than in normal tissues, and fascin overexpression correlated with the PDAC differentiation and prognosis. Fascin overexpression promoted PDAC cell migration and invasion by elevating matrix metalloproteinase-2 (MMP-2) expression. Fascin regulated MMP-2 expression through protein kinase C and extracellular signal-regulated kinase. Importantly, our data showed that hypoxia induced fascin overexpression in PDAC cells by promoting the binding of hypoxia-inducible factor-1 (HIF-1) to a hypoxia response element on the fascin promoter and transactivating fascin mRNA transcription. Intriguingly, HIF-1a expression levels in PDAC patient specimens significantly correlated with fascin expression. Moreover, immunohistochemistry staining of consecutive sections demonstrated colocalization between HIF-1a and fascin in PDAC specimens, suggesting that hypoxia and HIF-1a were responsible for fascin overexpression in PDAC. When ectopically expressed, fascin was able to rescue PDAC cell invasion after HIF-1a knockdown. Our results demonstrated that fascin is a direct target gene of HIF-1. Our data suggested that the hypoxic tumor microenvironment in PDAC might promote invasion and metastasis by inducing fascin overexpression, and fascin might be targeted to block PDAC progression. Cancer Res; 74(9);

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Section: Discussionmentioning

confidence: 99%

Hypoxia-Inducible Factor-1 Promotes Pancreatic Ductal Adenocarcinoma Invasion and Metastasis by Activating Transcription of the Actin-Bundling Protein Fascin

et al. 2014

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“…In contrast, fascin, as a prometastasis actin bundling protein, is a predictor of relatively worse prognosis in breast cancer [14] . On the basis of in vitro experimental results [9] , we hypothesised that GATA3 expression would reduce Smad4 expression and thereby also inhibit fascin expression in human breast cancer. Combined assessment of Smad4 and GATA3 expression provides more detailed information for predicting clinical outcomes in breast cancer than expression of either marker alone.…”

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confidence: 99%

“…Various proteins associated with Smad4 have been reported, but the regulatory mechanisms involving Smad4-interacting proteins remain unclear. A recent study demonstrated that GATA3 abrogated TGF-β-Smad signalling by abolishing the interactions between Smad4 and DNA elements linked to fascin function [9] . GATA3 is a zinc finger transcription factor that regulates tumour growth inhibition as well as the development and morphogenesis of the mammary glands [13] .…”

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Expression Pattern of Smad4/GATA3 as a Predictor of Survival in Invasive Ductal Carcinoma of the Breast

Min

Kim²,

Im³

et al. 2017

Pathobiology

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Background: Smad4 and GATA3 proteins are known prognostic markers in various cancers. Smad4 is a mediator linked to both tumour suppression and progression. GATA3 is a regulator of development and morphogenesis of the mammary gland. We assessed and compared the predictive performance of Smad4 and GATA3 for clinical outcomes in patients with breast cancer. Methods: The combined expression pattern based on Smad4+/- and GATA3+/- was evaluated by immunostaining using breast cancer tissue microarray, and the relationships between protein expression and clinicopathological variables were analysed. Results: Smad4 expression was only associated with an ill-defined tumour border, whereas GATA3 was associated with several good prognostic factors. On analysis of combined markers, there was a significant difference in the expression of fascin (an important factor for cancer invasiveness) between the Smad4+/GATA3- and Smad4-/GATA3+ groups. Smad4+/GATA3- was correlated with worse clinicopathological parameters, relapse-free survival (RFS), and overall survival (OS), compared to Smad4-/GATA3+. Conclusion: Combined markers of Smad4/GATA3 showed a superior performance compared to single markers for predicting RFS and OS in patients with breast cancer.

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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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GATA3 Transcription Factor Abrogates Smad4 Transcription Factor-mediated Fascin Overexpression, Invadopodium Formation, and Breast Cancer Cell Invasion

Cited by 48 publications

References 44 publications

Hypoxia-Inducible Factor-1 Promotes Pancreatic Ductal Adenocarcinoma Invasion and Metastasis by Activating Transcription of the Actin-Bundling Protein Fascin

Hypoxia-Inducible Factor-1 Promotes Pancreatic Ductal Adenocarcinoma Invasion and Metastasis by Activating Transcription of the Actin-Bundling Protein Fascin

Expression Pattern of Smad4/GATA3 as a Predictor of Survival in Invasive Ductal Carcinoma of the Breast

Monoubiquitination Inhibits the Actin Bundling Activity of Fascin

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