title: GLI1 inhibition promotes epithelial-to-mesenchymal transition in pancreatic cancer cells.
abstract: The Hedgehog (HH) pathway has been identified as an important deregulated signal transduction pathway in pancreatic ductal adenocarcinoma (PDAC), a cancer type characterized by a highly metastatic phenotype. In PDAC, the canonical HH pathway activity is restricted to the stromal compartment while HH signaling in the tumor cells is reduced as a consequence of constitutive KRAS activation. Here, we report that in the tumor compartment of PDAC the HH pathway effector transcription factor GLI1 regulates epithelial differentiation. RNAi-mediated knockdown of GLI1 abolished characteristics of epithelial differentiation, increased cell motility, and synergized with TGFβ to induce an epithelial-to-mesenchymal transition (EMT). Notably, EMT conversion in PDAC cells occurred in the absence of induction of SNAIL or SLUG, two canonical inducers of EMT in many other settings. Further mechanistic analysis revealed that GLI1 directly regulated the transcription of E-cadherin, a key determinant of epithelial tissue organization. Collectively, our findings identify GLI1 as an important positive regulator of epithelial differentiation, and they offer an explanation for how decreased levels of GLI1 are likely to contribute to the highly metastatic phenotype of PDAC.
authors.affiliation: Institute of Molecular Biology and Tumor Research, Philipps University, Marburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Joost
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.forename: Verena
authors.initials: V
authors.lastname: Rohnalter
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Holz
authors.forename: Anne M
authors.initials: AM
authors.lastname: Vrabel
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernandez-Barrena
authors.forename: Robert R
authors.initials: RR
authors.lastname: McWilliams
authors.forename: Michael
authors.initials: M
authors.lastname: Krause
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.forename: Matthias
authors.initials: M
authors.lastname: Lauth
mesh_terms: D022005:Adherens Junctions / Q000473:pathology; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D006801:Humans; D010190:Pancreatic Neoplasms / Q000473:pathology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1
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