title: Enhancing circadian clock function in cancer cells inhibits tumor growth.
abstract: Circadian clocks control cell cycle factors, and circadian disruption promotes cancer. To address whether enhancing circadian rhythmicity in tumor cells affects cell cycle progression and reduces proliferation, we compared growth and cell cycle events of B16 melanoma cells and tumors with either a functional or dysfunctional clock.
  
  
  
  We found that clock genes were suppressed in B16 cells and tumors, but treatments inducing circadian rhythmicity, such as dexamethasone, forskolin and heat shock, triggered rhythmic clock and cell cycle gene expression, which resulted in fewer cells in S phase and more in G1 phase. Accordingly, B16 proliferation in vitro and tumor growth in vivo was slowed down. Similar effects were observed in human colon carcinoma HCT-116 cells. Notably, the effects of dexamethasone were not due to an increase in apoptosis nor to an enhancement of immune cell recruitment to the tumor. Knocking down the essential clock gene Bmal1 in B16 tumors prevented the effects of dexamethasone on tumor growth and cell cycle events.
  
  
  
  Here we demonstrated that the effects of dexamethasone on cell cycle and tumor growth are mediated by the tumor-intrinsic circadian clock. Thus, our work reveals that enhancing circadian clock function might represent a novel strategy to control cancer progression.
authors.affiliation: Douglas Mental Health University Institute, Montreal, QC, H4H 1R3, Canada.|Department of Psychiatry, McGill University, Montreal, QC, H3A 1A1, Canada.|Present address: ZIEL Institute for Food and Health, Technical University of Munich, Freising, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Kiessling
authors.affiliation: Douglas Mental Health University Institute, Montreal, QC, H4H 1R3, Canada.
authors.forename: Lou
authors.initials: L
authors.lastname: Beaulieu-Laroche
authors.affiliation: Douglas Mental Health University Institute, Montreal, QC, H4H 1R3, Canada.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Blum
authors.affiliation: Center for Circadian Biology and Department of Psychiatry, University of California, San Diego, CA, 92037, USA.|Veterans Affairs San Diego Healthcare System, San Diego, CA, 92161, USA.
authors.forename: Dominic
authors.initials: D
authors.lastname: Landgraf
authors.affiliation: Center for Circadian Biology and Department of Psychiatry, University of California, San Diego, CA, 92037, USA.|Veterans Affairs San Diego Healthcare System, San Diego, CA, 92161, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Welsh
authors.affiliation: Douglas Mental Health University Institute, Montreal, QC, H4H 1R3, Canada.|Department of Psychiatry, McGill University, Montreal, QC, H3A 1A1, Canada.
authors.forename: Kai-Florian
authors.initials: KF
authors.lastname: Storch
authors.affiliation: Maisonneuve-Rosemont Hospital Research Centre, Montreal, QC, H1T 2M4, Canada.|Department of Medicine, University of Montreal, Montreal, QC, H3T 1J4, Canada.|Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, QC, H3T 1J4, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Labrecque
authors.affiliation: Douglas Mental Health University Institute, Montreal, QC, H4H 1R3, Canada. nicolas.cermakian@mcgill.ca.|Department of Psychiatry, McGill University, Montreal, QC, H3A 1A1, Canada. nicolas.cermakian@mcgill.ca.
authors.forename: Nicolas
authors.identifier: 0000-0003-4517-9131
authors.initials: N
authors.lastname: Cermakian
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057906:Circadian Clocks / Q000187:drug effects / Q000235:genetics; D002940:Circadian Rhythm / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D018869:Heat-Shock Response / Q000187:drug effects; D006801:Humans; D008546:Melanoma, Experimental / Q000235:genetics* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008954:Models, Biological
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D005576:Colforsin; D003907:Dexamethasone
keywords: Cell cycle checkpoints; Circadian clock; Clock gene expression; Melanoma cancer; Tumor growth