title: Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells.
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.
authors.affiliation: Laboratory of Molecular Tumor Pathology, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Jürchott
authors.forename: Ralf-Jürgen
authors.initials: RJ
authors.lastname: Kuban
authors.forename: Till
authors.initials: T
authors.lastname: Krech
authors.forename: Nils
authors.initials: N
authors.lastname: Blüthgen
authors.forename: Ulrike
authors.initials: U
authors.lastname: Stein
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Walther
authors.forename: Christian
authors.initials: C
authors.lastname: Friese
authors.forename: Szymon M
authors.initials: SM
authors.lastname: Kiełbasa
authors.forename: Ute
authors.initials: U
authors.lastname: Ungethüm
authors.forename: Per
authors.initials: P
authors.lastname: Lund
authors.forename: Thomas
authors.initials: T
authors.lastname: Knösel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kemmner
authors.forename: Markus
authors.initials: M
authors.lastname: Morkel
authors.forename: Johannes
authors.initials: J
authors.lastname: Fritzmann
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schlag
authors.forename: Walter
authors.initials: W
authors.lastname: Birchmeier
authors.forename: Tammo
authors.initials: T
authors.lastname: Krueger
authors.forename: Silke
authors.initials: S
authors.lastname: Sperling
authors.forename: Christine
authors.initials: C
authors.lastname: Sers
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Royer
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Herzel
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schäfer
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005809:Genes, Regulator; D006801:Humans; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051840:Y-Box-Binding Protein 1; D020929:Mitogen-Activated Protein Kinase Kinases