NFAT-Induced Histone Acetylation Relay Switch Promotes c-Myc-Dependent Growth in Pancreatic Cancer Cells

Alexander Köenig, Thomas Linhart, Katrin Schlengemann, Kristina Reutlinger, Jessica Wegele, Guido Adler, Garima Singh, Leonie Hofmann, Steffen Kunsch, Thomas Büch, Eva Schäfer, Thomas M. Gress, Martin E. Fernandez-Zapico, Volker Ellenrieder

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

Background & Aims: Induction of immediate early transcription factors (ITF) represents the first transcriptional program controlling mitogen-stimulated cell cycle progression in cancer. Here, we examined the transcriptional mechanisms regulating the ITF protein c-Myc and its role in pancreatic cancer growth in vitro and in vivo. Methods: Expression of ITF proteins was examined by reverse-transcription polymerase chain reaction and immunoblotting, and its implications in cell cycle progression and growth was determined by flow cytometry and [3H]-thymidine incorporation. Intracellular Ca2+ concentrations, calcineurin activity, and cellular nuclear factor of activated T cells (NFAT) distribution were analyzed. Transcription factor complex formations and promoter regulation were examined by immunoprecipitations, reporter gene assays, and chromatin immunoprecipitation. Using a combination of RNA interference knockdown technology and xenograft models, we analyzed the significance for pancreatic cancer tumor growth. Results: Serum promotes pancreatic cancer growth through induction of the proproliferative NFAT/c-Myc axis. Mechanistically, serum increases intracellular Ca2+ concentrations and activates the calcineurin/NFAT pathway to induce c-Myc transcription. NFAT binds to a serum responsive element within the proximal promoter, initiates p300-dependent histone acetylation, and creates a local chromatin structure permissive for the inducible recruitment of Ets-like gene (ELK)-1, a protein required for maximal activation of the c-Myc promoter. The functional significance of this novel pathway was emphasized by impaired c-Myc expression, G1 arrest, and reduced tumor growth upon NFAT depletion in vitro and in vivo. Conclusions: Our study uncovers a novel mechanism regulating cell growth and identifies the NFAT/ELK complex as modulators of early stages of mitogen-stimulated proliferation in pancreatic cancer cells.

Original languageEnglish (US)
Pages (from-to)1189-1199.e2
JournalGastroenterology
Volume138
Issue number3
DOIs
StatePublished - Mar 2010

Keywords

  • NFAT
  • Pancreatic Cancer
  • Transcription
  • c-Myc

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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