Journal
GASTROENTEROLOGY
Volume 138, Issue 3, Pages 1189-U487Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2009.10.045
Keywords
Pancreatic Cancer; c-Myc; NFAT; Transcription
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [SFB-TR17]
- German Cancer Research Foundation [70-3022-El I]
- Miles and Shirley Fiterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, Division of Oncology Research, Mayo Clinic Cancer Center [P50 CA102701, CA136526]
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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 [H-3]-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.
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