title: Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity.
abstract: The ability of exocrine pancreatic cells to change the cellular phenotype is required for tissue regeneration upon injury, but also contributes to their malignant transformation and tumor progression. We investigated context-dependent signaling and transcription mechanisms that determine pancreatic cell fate decisions toward regeneration and malignancy. In particular, we studied the function and regulation of the inflammatory transcription factor nuclear factor of activated T cells 1 (NFATC1) in pancreatic cell plasticity and tissue adaptation.
  
  
  
  We analyzed cell plasticity during pancreatic regeneration and transformation in mice with pancreas-specific expression of a constitutively active form of NFATC1, or depletion of enhancer of zeste 2 homologue 2 (EZH2), in the context of wild-type or constitutively activate Kras, respectively. Acute and chronic pancreatitis were induced by intraperitoneal injection of caerulein. EZH2-dependent regulation of NFATC1 expression was studied in mouse in human pancreatic tissue and cells by immunohistochemistry, immunoblotting, and quantitative reverse transcription polymerase chain reaction. We used genetic and pharmacologic approaches of EZH2 and NFATC1 inhibition to study the consequences of pathway disruption on pancreatic morphology and function. Epigenetic modifications on the NFATC1 gene were investigated by chromatin immunoprecipitation assays.
  
  
  
  NFATC1 was rapidly and transiently induced in early adaptation to acinar cell injury in human samples and in mice, where it promoted acinar cell transdifferentiation and blocked proliferation of metaplastic pancreatic cells. However, in late stages of regeneration, Nfatc1 was epigenetically silenced by EZH2-dependent histone methylation, to enable acinar cell redifferentiation and prevent organ atrophy and exocrine insufficiency. In contrast, oncogenic activation of KRAS signaling in pancreatic ductal adenocarcinoma cells reversed the EZH2-dependent effects on the NFATC1 gene and was required for EZH2-mediated transcriptional activation of NFATC1.
  
  
  
  In studies of human and mouse pancreatic cells and tissue, we identified context-specific epigenetic regulation of NFATc1 activity as an important mechanism of pancreatic cell plasticity. Inhibitors of EZH2 might therefore interfere with oncogenic activity of NFATC1 and be used in treatment of pancreatic ductal adenocarcinoma.
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Germany.
authors.forename: Nai-Ming
authors.initials: NM
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Neesse
authors.affiliation: Signaling and Transcription Laboratory, Department of Gastroenterology, Philipp's University, Marburg, Germany.
authors.forename: Moritz Lino
authors.initials: ML
authors.lastname: Dyck
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Steuber
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Germany.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Koenig
authors.affiliation: II. Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität, Munich, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Lubeseder-Martellato
authors.affiliation: Signaling and Transcription Laboratory, Department of Gastroenterology, Philipp's University, Marburg, Germany.
authors.forename: Thore
authors.initials: T
authors.lastname: Winter
authors.affiliation: Signaling and Transcription Laboratory, Department of Gastroenterology, Philipp's University, Marburg, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Forster
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Germany.
authors.forename: Hanibal
authors.initials: H
authors.lastname: Bohnenberger
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kitz
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Reuter-Jessen
authors.affiliation: Department of Internal Medicine I, University Medical Center Halle, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Griesmann
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Gaedcke
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Germany.
authors.forename: Marian
authors.initials: M
authors.lastname: Grade
authors.affiliation: Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota; School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, PR China.
authors.forename: Jin-San
authors.initials: JS
authors.lastname: Zhang
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wan-Chi
authors.initials: WC
authors.lastname: Tsai
authors.affiliation: German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Siveke
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schildhaus
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Germany.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Ellenrieder
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Germany. Electronic address: elisabeth.hessmann@med.uni-goettingen.de.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hessmann
mesh_terms: D061354:Acinar Cells / Q000502:physiology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000737:chemistry / Q000235:genetics*; D000066670:Cell Plasticity / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D054338:Cell Transdifferentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002108:Ceruletide; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D050778:NFATC Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D010179:Pancreas / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000235:genetics*; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000503:physiopathology; D011401:Promoter Regions, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D050778:NFATC Transcription Factors; D002108:Ceruletide; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: EZH2; Epigenetic Gene Regulation; Histone Methyltransferase; Oncogene; Pancreatic Cancer