title: Ras-mediated deregulation of the circadian clock in cancer.
abstract: Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.
authors.affiliation: Institute for Theoretical Biology, Charité - Universitätsmedizin and Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Relógio
authors.affiliation: Knowledge Management in Bioinformatics, Institute for Computer Science, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Philippe
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Laboratory of Molecular Tumor Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Laboratory of Chronobiology, Institute for Medical Immunology Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Paula
authors.initials: P
authors.lastname: Medina-Pérez
authors.affiliation: Laboratory of Chronobiology, Institute for Medical Immunology Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Reischl
authors.affiliation: Institute for Theoretical Biology, Charité - Universitätsmedizin and Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Sander
authors.initials: S
authors.lastname: Bervoets
authors.affiliation: Laboratory of Molecular Tumor Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ewa
authors.initials: E
authors.lastname: Gloc
authors.affiliation: Laboratory of Molecular Tumor Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Pamela
authors.initials: P
authors.lastname: Riemer
authors.affiliation: Laboratory of Molecular Tumor Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Shila
authors.initials: S
authors.lastname: Mang-Fatehi
authors.affiliation: Laboratory of Chronobiology, Institute for Medical Immunology Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Bert
authors.initials: B
authors.lastname: Maier
authors.affiliation: Laboratory of Molecular Tumor Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schäfer
authors.affiliation: Knowledge Management in Bioinformatics, Institute for Computer Science, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Leser
authors.affiliation: Institute for Theoretical Biology, Charité - Universitätsmedizin and Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Herzel
authors.affiliation: Laboratory of Chronobiology, Institute for Medical Immunology Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Kramer
authors.affiliation: Laboratory of Molecular Tumor Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Sers
mesh_terms: D045744:Cell Line, Tumor; D057906:Circadian Clocks / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D018631:ras Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins