Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells

• Published in: PLoS genetics Vol. 6; no. 12; p. e1001231
• Main Authors: Jürchott, Karsten, Kuban, Ralf-Jürgen, Krech, Till, Blüthgen, Nils, Stein, Ulrike, Walther, Wolfgang, Friese, Christian, Kiełbasa, Szymon M, Ungethüm, Ute, Lund, Per, Knösel, Thomas, Kemmner, Wolfgang, Morkel, Markus, Fritzmann, Johannes, Schlag, Peter M, Birchmeier, Walter, Krueger, Tammo, Sperling, Silke, Sers, Christine, Royer, Hans-Dieter, Herzel, Hanspeter, Schäfer, Reinhold
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2010; Public Library of Science (PLoS)
• Subjects: Cell Biology; Cell Line, Tumor; Chemical properties; Colorectal cancer; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Computational Biology/Genomics; DNA binding proteins; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes; Genes, Regulator; Genetic aspects; Genetics and Genomics/Cancer Genetics; Genomes; Humans; Integrated approach; Kinases; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases - genetics; Mitogen-Activated Protein Kinase Kinases - metabolism; Molecular Biology/Bioinformatics; Oncology/Gastrointestinal Cancers; Ontology; Pathology/Molecular Pathology; Physiological aspects; Protein kinases; Proteins; Risk factors; Signal transduction; Y-Box-Binding Protein 1 - genetics; Y-Box-Binding Protein 1 - metabolism; Germany
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1001231

Transcriptional signatures are an indispensible source of correlative information on disease-related molecular alterations on a genome-wide level. Numerous candidate genes involved in disease and in factors of predictive, as well as of prognostic, value have been deduced from such molecular portraits, e.g. in cancer. However, mechanistic insights into the regulatory principles governing global transcriptional changes are lagging behind extensive compilations of deregulated genes. To identify regulators of transcriptome alterations, we used an integrated approach combining transcriptional profiling of colorectal cancer cell lines treated with inhibitors targeting the receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase pathway, computational prediction of regulatory elements in promoters of co-regulated genes, chromatin-based and functional cellular assays. We identified commonly co-regulated, proliferation-associated target genes that respond to the MAPK pathway. We recognized E2F and NFY transcription factor binding sites as prevalent motifs in those pathway-responsive genes and confirmed the predicted regulatory role of Y-box binding protein 1 (YBX1) by reporter gene, gel shift, and chromatin immunoprecipitation assays. We also validated the MAPK-dependent gene signature in colorectal cancers and provided evidence for the association of YBX1 with poor prognosis in colorectal cancer patients. This suggests that MEK/ERK-dependent, YBX1-regulated target genes are involved in executing malignant properties.