Ras-mediated deregulation of the circadian clock in cancer

PLoS Genet. 2014 May 29;10(5):e1004338. doi: 10.1371/journal.pgen.1004338. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Circadian Clocks / genetics*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Proto-Oncogene Proteins / biosynthesis*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Signal Transduction
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • ras Proteins / biosynthesis*
  • ras Proteins / genetics

Substances

  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Mitogen-Activated Protein Kinase Kinases
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins

Grant support

This work was funded by the BMBF (ColoNET; grant to AK, CS, HH, PT, RS, UL, and OncoPATH grant to CS, PR, RS, UL), the Berliner Krebsgesellschaft (grant to EG), the Rahel-Hirsch fellowship of Charité Universitätsmedizin Berlin (grant to AR) and the Deutsche Forschungsgemeinschaft (SFB 618/A1 A3 A4). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.