GLI1-dependent transcriptional repression of CYLD in basal cell carcinoma

Kuphal, Silke; Shaw-Hallgren, Gina; Eberl, Markus; Karrer, Sigrid; Aberger, Fritz; Bosserhoff, Anja‐Katrin; Massoumi, Ramin

doi:10.1038/onc.2011.163

Cited by 33 publications

(29 citation statements)

References 27 publications

(31 reference statements)

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“…10). Previous studies have reported that SNAI1 is required for cell proliferation in malignant melanoma (57,58) and ZEB1 induces proliferation and tube formation through upregulation of VEGF in human umbilical vein endothelial cells (59). It has also been reported that SNAI and ZEB family members inhibit cell cycle progression, resulting in accumulation of cells in G1 phase of cell cycle in epidermoid A431 cells (60).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 2 induces proliferation and fibrosis via SNAI1-mediated activation of CDK2 and ZEB1 in corneal endothelium

Lee

Jung

Heur

2018

Journal of Biological Chemistry

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Investigating stimulation of endogenous wound healing in corneal endothelial cells (CECs) may help address the global shortage of donor corneas by decreasing the number of transplants performed for blindness due to endothelial dysfunction. We previously reported that IL-1β stimulation leads to fibroblast growth factor (FGF2) expression, enhancing migration and proliferation of mammalian CECs. However, FGF2 also promotes the endothelial-mesenchymal transition, which can lead to retrocorneal membrane formation and blindness. This prompted us to investigate downstream FGF2 signaling targets that could be manipulated to prevent retrocorneal membrane formation. FGF2 stimulation altered cell morphology and induced expression of mesenchymal transition marker genes such as snail family transcriptional repressor 1 (SNAI1), SNAI2, zinc finger E-boxbinding homeobox 1 (ZEB1), and ZEB2. This, in turn, induced expression of fibronectin, vimentin and, type I collagen and suppressed E-cadherin in CECs in vitro and ex vivo. siRNA-mediated SNAI1 knockdown revealed that SNAI1 induces ZEB1 expression, in turn inducing expression of type I collagen, the major component of retrocorneal membranes, and of cyclin-dependent kinase 2 (CDK2) and cyclin E1, promoting cell proliferation. siRNA-mediated knockdown of SNAI1 or ZEB1, but not of CDK2, inhibited FGF2-dependent expression of fibronectin, vimentin, and type I collagen and of suppression of E-cadherin expression. We conclude that SNAI1 is a key regulator of FGF2-dependent mesenchymal transition in human ex vivo corneal endothelium, with ZEB1 regulating type I collagen expression and CDK2 regulating cell proliferation. These results suggest that SNAI1 promotes fibrosis and cell proliferation in human corneal endothelium through ZEB1 and CDK2.The cornea is the anterior, transparent tissue of the human eye and consists of epithelium, stroma and endothelium. The corneal endothelium is composed of a monolayer of cells and plays a critical role in maintaining corneal transparency that is critical for sharp vision through its pump function (1,2). Adult human corneal endothelial cells (CEC) are usually mitotically inactive and arrested at the G 1 phase of the cell cycle (3,4). Because of the cell cycle arrest, there is a progressive decline in CEC density that can be further accelerated by injury, such as intraocular surgery or infection. When the density decreases below a critical threshold, corneal edema ensues, leading to loss of transparency and vision. Vision loss secondary to endothelial dysfunction is a common indication for corneal transplantation in developed nations.There have been many attempts to overcome the cell cycle arrest using various approaches including the use of growth factors such as FGF, EGF, and TGF-β, the use of endothelial cell growth supplements (5-9), and disruption of contact inhibition using EDTA (10). Moreover, severely injured CEC can undergo mesenchymal transition through which they lose their polarity and assume a fibroblastic phenotype. These CEC a...

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Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 2 induces proliferation and fibrosis via SNAI1-mediated activation of CDK2 and ZEB1 in corneal endothelium

Lee

Jung

Heur

2018

Journal of Biological Chemistry

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“…This is deemed to be due to CYLD’s role in checking inflammation which has been demonstrated in many types of cancer [17, 18, 34, 35, 57–60]. Since NF-kB-mediated inflammation is widely known to cause the generation of tissue damaging reactive oxygen species, inflammatory cytokine cascades and recruitment of immune cells (which release factors like granzymes and superoxides), it is logical that CYLD’s ability to cut off NF-kB activation would limit subsequent damage.…”

Section: Cyld Overviewmentioning

confidence: 99%

“…RhoA, in particular, was found to be controlled by CYLD through action on LARG (Leukemia Associate RhoGEF) [86]. Basal cell carcinoma, one of the most common cancers in humans, was shown to downregulate CYLD transcript by the action of the Snail transcription factor, which is in turn activated by the Kruppel zinc finger gene GLI1 [32, 35]. This downregulation affected the keratinocyte cancer cells by increasing their proliferation, which could no longer be controlled by CYLD.…”

Section: Cyld Functionmentioning

confidence: 99%

CYLD-Mediated Signaling and Diseases

Mathis¹,

Lai²,

Qu³

et al. 2015

CDT

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The conserved cylindromatosis (CYLD) codes for a deubiquitinating enzyme and is a crucial regulator of diverse cellular processes such as immune responses, inflammation, death, and proliferation. It directly regulates multiple key signaling cascades, such as the Nuclear Factor kappa B [NF-kB] and the Mitogen-Activated Protein Kinase (MAPK) pathways, by its catalytic activity on polyubiquitinated key intermediates. Several lines of emerging evidence have linked CYLD to the pathogenesis of various maladies, including cancer, poor infection control, lung fibrosis, neural development, and now cardiovascular dysfunction. While CYLD-mediated signaling is cell type and stimuli specific, the activity of CYLD is tightly controlled by phosphorylation and other regulators such as Snail. This review explores a broad selection of current and past literature regarding CYLD’s expression, function and regulation with emerging reports on its role in cardiovascular disease.

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“…Furthermore, inhibition of the dysregulated tropomyosin kinase TRK has also been proposed as a strategy to treat tumors with loss of CYLD (Rajan et al, 2011). In a different approach, it has been recently suggested that downregulation of Snail (a CYLD repressor) through inhibition of its activator GLI1 could reverse the dramatically reduced expression of CYLD in basal cell carcinomas (Kuphal et al, 2011). Finally, exploiting concepts such as synthetic lethality could facilitate the identification of novel therapeutic targets in the DUB family.…”

Section: Targeting Dubs In Cancermentioning

confidence: 99%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

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Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

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GLI1-dependent transcriptional repression of CYLD in basal cell carcinoma

Cited by 33 publications

References 27 publications

Fibroblast growth factor 2 induces proliferation and fibrosis via SNAI1-mediated activation of CDK2 and ZEB1 in corneal endothelium

Fibroblast growth factor 2 induces proliferation and fibrosis via SNAI1-mediated activation of CDK2 and ZEB1 in corneal endothelium

CYLD-Mediated Signaling and Diseases

Deubiquitinases in cancer: new functions and therapeutic options

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