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

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Item Type:Article
Title:Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells
Creators Name:Juerchott, K. and Kuban, R.J. and Krech, T. and Bluethgen, N. and Stein, U. and Walther, W. and Friese, C. and Kielbasa, S.M. and Ungethuem, U. and Lund, P. and Knoesel, T. and Kemmner, W. and Morkel, M. and Fritzmann, J. and Schlag, P.M. and Birchmeier, W. and Krueger, T. and Sperling, S. and Sers, C. and Royer, H.D. and Herzel, H. and Schaefer, R.
Abstract: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.
Keywords:Colorectal Neoplasms, Gene Expression Profiling, Regulator Genes, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase Kinases, Neoplastic Gene Expression Regulation, Tumor Cell Line, Y-Box-Binding Protein 1
Source:PLoS Genetics
ISSN:1553-7390
Publisher:Public Library of Science (U.S.A.)
Volume:6
Number:12
Page Range:e1001231
Date:2 December 2010
Official Publication:https://doi.org/10.1371/journal.pgen.1001231
PubMed:View item in PubMed

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