The Transcription Factor GLI1 Interacts with SMAD Proteins to Modulate Transforming Growth Factor β-Induced Gene Expression in a p300/CREB-binding Protein-associated Factor (PCAF)-dependent Manner

Nye, Monica D.; Almada, Luciana L.; Fernández‐Barrena, Maite G.; Marks, David L.; Elsawa, Sherine F.; Vrabel, Anne M.; Tolosa, Ezequiel J.; Ellenrieder, Volker; Fernández-Zapico, Martín E.

doi:10.1074/jbc.m113.545194

Cited by 56 publications

(48 citation statements)

References 52 publications

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“…As additional regulators of GLI1 activity, the SMAD2/SMAD4 and ZIC2 proteins play important roles in PDAC cells (Fig. ) . As previously mentioned, TGFβ induces SMAD3‐mediated expression of GLI2 , and consequently, the expression of GLI1 .…”

Section: Hedgehog Signaling: How It Came Onstage?mentioning

confidence: 81%

“…Importantly, GLI1 has been proved to directly transactivate the expression of genes that are associated with most of these cellular functions. For instance, GLI1 directly up‐regulates the expression of CCND1 (cyclin D1), and also DNA methyltransferase DNMT1, which enhances the promoter methylation of CDKN1B (encoding p27 Kip1 ) and CDKN2C (encoding p18 INK4c ), accelerating cell‐cycle progression of PDAC cells . As for a genome instability and mutation, GLI1 directly up‐regulates BHLHE41 expression in PDAC cells .…”

Section: Hedgehog Signaling: How It Came Onstage?mentioning

confidence: 99%

“…As previously mentioned, TGFβ induces SMAD3‐mediated expression of GLI2 , and consequently, the expression of GLI1 . TGFβ also enhances the GLI1‐mediated expression of BCL2 through the SMAD2/SMAD4 cascade in PDAC cells; the SMAD2/SMAD4 proteins associate with GLI1 and recruit GLI1 to the GBS of the BCL2 promoter . However, naive SMAD4 protein is absent in approximately half of PDAC cases; therefore, TGFβ‐stimulated GLI1 target gene profiles should be compared between SMAD4‐intact and SMAD4‐deleted PDAC cells.…”

Section: Hedgehog Signaling: How It Came Onstage?mentioning

confidence: 99%

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GLI1, a master regulator of the hallmark of pancreatic cancer

Kasai

2016

Pathology International

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Hedgehog signaling is highly conserved across species and governs proper embryonic development. Germline gene mutations that reduce this signaling activity cause a variety of developmental abnormalities such as holoprosencephaly, while those that enhance Hedgehog signaling activity induce a tumor-predisposition condition Nevoid basal cell carcinoma syndrome. Furthermore, dysregulated activation of Hedgehog signaling has been recognized in various sporadic malignancies, including pancreatic adenocarcinoma. Pancreatic adenocarcinoma develops through a multistep carcinogenesis starting with oncogenic mutation of the KRAS gene. During this process, precancerous or cancer cells secrete Hedgehog ligand proteins to promote characteristic desmoplastic stroma around the cells, which in turn activates the expression of the downstream transcription factor GLI1 inside the cells. The quantitative and spatiotemporal dysregulation of GLI1 subsequently leads to the expression of transcriptional target genes of GLI1 that govern the hallmark of malignant properties. Here, after a brief introductory outline, a perspective is offered of Hedgehog signaling with a special focus on the role of GLI1 in pancreatic carcinogenesis.

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Section: Hedgehog Signaling: How It Came Onstage?mentioning

confidence: 81%

Section: Hedgehog Signaling: How It Came Onstage?mentioning

confidence: 99%

Section: Hedgehog Signaling: How It Came Onstage?mentioning

confidence: 99%

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GLI1, a master regulator of the hallmark of pancreatic cancer

Kasai

2016

Pathology International

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“…Previous studies have revealed that in order to activate gene expression, Gli1 works within epigenetic complexes that decorate histone tails with various activating or repressive marks[36]. To expand on this knowledge, we performed differential expression analysis of RNA sequencing data from a variety of sources of cholangiocytes: 1) iDC; 2) the NHC cell line; and 3) isolated human cholangiocytes (IHC).…”

Section: Resultsmentioning

confidence: 99%

Hedgehog Signaling Overcomes an EZH2-Dependent Epigenetic Barrier to Promote Cholangiocyte Expansion

Jalan‐Sakrikar

Assuncao

et al. 2016

PLoS ONE

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Background & AimsDevelopmental morphogens play an important role in coordinating the ductular reaction and portal fibrosis occurring in the setting of cholangiopathies. However, little is known about how membrane signaling events in ductular reactive cells (DRCs) are transduced into nuclear transcriptional changes to drive cholangiocyte maturation and matrix deposition. Therefore, the aim of this study was to investigate potential mechanistic links between cell signaling events and epigenetic regulators in DRCs.MethodsUsing directed differentiation of induced pluripotent stem cells (iPSC), isolated DRCs, and in vivo models, we examine the mechanisms whereby sonic hedgehog (Shh) overcomes an epigenetic barrier in biliary precursors and promotes both cholangiocyte maturation and deposition of fibronectin (FN).ResultsWe demonstrate, for the first time, that Gli1 influences the differentiation state and fibrogenic capacity of iPSC-derived hepatic progenitors and isolated DRCs. We outline a novel pathway wherein Shh-mediated Gli1 binding in key cholangiocyte gene promoters overcomes an epigenetic barrier conferred by the polycomb protein, enhancer of zeste homolog 2 (EZH2) and initiates the transcriptional program of cholangiocyte maturation. We also define previously unknown functional Gli1 binding sites in the promoters of cytokeratin (CK)7, CK19, and FN. Our in vivo results show that EZH2 KO mice fed the choline-deficient, ethanolamine supplemented (CDE) diet have an exaggerated cholangiocyte expansion associated with more robust ductular reaction and increased peri-portal fibrosis.ConclusionWe conclude that Shh/Gli1 signaling plays an integral role in cholangiocyte maturation in vitro by overcoming an EZH2-dependent epigenetic barrier and this mechanism also promotes biliary expansion in vivo.

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“…GLI1 expression construct and siRNA targeting GLI1 were described previously (35). The GLI-luciferase reporter containing eight consecutive GLI binding sites upstream of the luciferase gene (GLI-LUC) was kindly provided by Dr. Chi-chung Hui (University of Toronto, Toronto, Ontario, Canada).…”

Section: Methodsmentioning

confidence: 99%

Nuclear Factor of Activated T Cells-dependent Down-regulation of the Transcription Factor Glioma-associated Protein 1 (GLI1) Underlies the Growth Inhibitory Properties of Arachidonic Acid

Comba

Almada

Tolosa

et al. 2016

Journal of Biological Chemistry

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Numerous reports have demonstrated a tumor inhibitory effect of polyunsaturated fatty acids (PUFAs). However, the molecular mechanisms modulating this phenomenon are in part poorly understood. Here, we provide evidence of a novel antitumoral mechanism of the PUFA arachidonic acid (AA). In vivo and in vitro experiments showed that AA treatment decreased tumor growth and metastasis and increased apoptosis. Molecular analysis of this effect showed significantly reduced expression of a subset of antiapoptotic proteins, including BCL2, BFL1/A1, and 4-1BB, in AA-treated cells. We demonstrated that down-regulation of the transcription factor gliomaassociated protein 1 (GLI1) in AA-treated cells is the underlying mechanism controlling BCL2, BFL1/A1, and 4-1BB expression. Using luciferase reporters, chromatin immunoprecipitation, and expression studies, we found that GLI1 binds to the promoter of these antiapoptotic molecules and regulates their expression and promoter activity. We provide evidence that AA-induced apoptosis and down-regulation of antiapoptotic genes can be inhibited by overexpressing GLI1 in AA-sensitive cells. Conversely, inhibition of GLI1 mimics AA treatments, leading to decreased tumor growth, cell viability, and expression of antiapoptotic molecules. Further characterization showed that AA represses GLI1 expression by stimulating nuclear translocation of NFATc1, which then binds the GLI1 promoter and represses its transcription. AA was shown to increase reactive oxygen species. Treatment with antioxidants impaired the AAinduced apoptosis and down-regulation of GLI1 and NFATc1 activation, indicating that NFATc1 activation and GLI1 repression require the generation of reactive oxygen species. Collectively, these results define a novel mechanism underlying AA antitumoral functions that may serve as a foundation for future PUFA-based therapeutic approaches.

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The Transcription Factor GLI1 Interacts with SMAD Proteins to Modulate Transforming Growth Factor β-Induced Gene Expression in a p300/CREB-binding Protein-associated Factor (PCAF)-dependent Manner

Cited by 56 publications

References 52 publications

GLI1, a master regulator of the hallmark of pancreatic cancer

GLI1, a master regulator of the hallmark of pancreatic cancer

Hedgehog Signaling Overcomes an EZH2-Dependent Epigenetic Barrier to Promote Cholangiocyte Expansion

Nuclear Factor of Activated T Cells-dependent Down-regulation of the Transcription Factor Glioma-associated Protein 1 (GLI1) Underlies the Growth Inhibitory Properties of Arachidonic Acid

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