Identification of Y-Box Binding Protein 1 As a Core Regulator of MEK/ERK Pathway-Dependent Gene Signatures in Colorectal Cancer Cells

• DOI: 10.1371/journal.pgen.1001231
• Publication Date: 2010-12-02T20:55:03Z
• Authors: Karsten Jürchott; Ralf-Jürgen Kuban; Till Krech; Nils Blüthgen; Ulrike Stein; Wolfgang Walther; Christian Friese; Szymon M. Kiełbasa; Ute Ungethüm; Per Lund; Thomas Knösel; Wolfgang Kemmner; Markus Morkel; Johannes Fritzmann; Peter M. Schlag; Walter Birchmeier; Tammo Krueger; Silke Sperling; Christine Sers; Hans-Dieter Royer; Hanspeter Herzel; Reinhold Schäfer
• Keywords: Mitogen-Activated Protein Kinase Kinases; Cancer Research; 0303 health sciences; MAP Kinase Signaling System; Gene Expression Profiling; QH426-470; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Cell Line, Tumor; Genes, Regulator; Genetics; Humans; Y-Box-Binding Protein 1; Colorectal Neoplasms; Research Article

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.