Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity

Nai Ming Chen, Albrecht Neesse, Moritz Lino Dyck, Benjamin Steuber, Alexander O. Koenig, Clara Lubeseder-Martellato, Thore Winter, Teresa Forster, Hanibal Bohnenberger, Julia Kitz, Kirsten Reuter-Jessen, Heidi Griesmann, Jochen Gaedcke, Marian Grade, Jin San Zhang, Wan Chi Tsai, Jens Siveke, Hans Ulrich Schildhaus, Philipp Ströbel, Steven JohnsenVolker Ellenrieder, Elisabeth Hessmann

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Background & Aims 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. Methods 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. Results 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. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)1507-1520.e15
JournalGastroenterology
Volume152
Issue number6
DOIs
StatePublished - May 1 2017
Externally publishedYes

Keywords

  • Epigenetic Gene Regulation
  • EZH2
  • Histone Methyltransferase
  • Oncogene
  • Pancreatic Cancer

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Chen, N. M., Neesse, A., Dyck, M. L., Steuber, B., Koenig, A. O., Lubeseder-Martellato, C., Winter, T., Forster, T., Bohnenberger, H., Kitz, J., Reuter-Jessen, K., Griesmann, H., Gaedcke, J., Grade, M., Zhang, J. S., Tsai, W. C., Siveke, J., Schildhaus, H. U., Ströbel, P., ... Hessmann, E. (2017). Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity. Gastroenterology, 152(6), 1507-1520.e15. https://doi.org/10.1053/j.gastro.2017.01.043