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

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

Gastroenterology (New York, N.Y. 1943), 2010-03, Vol.138 (3), p.1189-1199.e2 [Periódico revisado por pares]

United States: Elsevier Inc

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NFAT-Induced Histone Acetylation Relay Switch Promotes c-Myc-Dependent Growth in Pancreatic Cancer Cells
Autor: Köenig, Alexander ; Linhart, Thomas ; Schlengemann, Katrin ; Reutlinger, Kristina ; Wegele, Jessica ; Adler, Guido ; Singh, Garima ; Hofmann, Leonie ; Kunsch, Steffen ; Büch, Thomas ; Schäfer, Eva ; Gress, Thomas M ; Fernandez–Zapico, Martin E ; Ellenrieder, Volker
Assuntos: Acetylation ; Adenocarcinoma - genetics ; Adenocarcinoma - metabolism ; Adenocarcinoma - pathology ; Animals ; Binding Sites ; Blotting, Western ; c-Myc ; Calcineurin - metabolism ; Calcium - metabolism ; Cell Cycle ; Cell Line, Tumor ; Cell Proliferation ; Chromatin Assembly and Disassembly ; Chromatin Immunoprecipitation ; ets-Domain Protein Elk-1 - metabolism ; Flow Cytometry ; Gastroenterology and Hepatology ; Histones - metabolism ; Humans ; Immunohistochemistry ; Male ; Mice ; Mice, Nude ; Neoplasm Transplantation ; NFAT ; NFATC Transcription Factors - genetics ; NFATC Transcription Factors - metabolism ; p300-CBP Transcription Factors - metabolism ; Pancreatic Cancer ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-myc - genetics ; Proto-Oncogene Proteins c-myc - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA Interference ; Serum - metabolism ; Serum Response Element ; Signal Transduction ; Time Factors ; Transcription ; Transcription, Genetic ; Transfection
É parte de: Gastroenterology (New York, N.Y. 1943), 2010-03, Vol.138 (3), p.1189-1199.e2
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Alexander König: drafting of the manuscript, acquisition of data
A.K and T.L. contributed equally to the manuscript
Katrin Schlengemann: acquisition of data
Leonie Hofmann: acquisition of data
Eva Schäfer: acquisition of data
Volker Ellenrieder: study concept and design, interpretation of data, obtained funding, critical revision of the manuscript for important intellectual content, study supervision
Garima Singh: acquisition of data
Thomas Büch: interpretation of data, statistical analysis
Thomas M. Gress: critical revision of the manuscript
Kristina Reutlinger: technical support
Jessica Wegele: technical support
Martin E. Fernandez-Zapico: acquisition of data, study concept and design analysis and interpretation of data, obtained funding
Thomas Linhart: acquisition of data
Steffen Kunsch: statistical analysis, analysis and interpretation of data
Guido Adler: critical revision of the manuscript for important intellectual content
Descrição: 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 [3 H]-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.
Editor: United States: Elsevier Inc
Idioma: Inglês

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

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

United States: Elsevier Inc

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