title: Epigenetic silencing of the candidate tumor suppressor gene Per1 in non-small cell lung cancer.
abstract: OBJECTIVE
  Epigenetic events are a critical factor contributing to cancer development. The purpose of this study was to identify tumor suppressor genes silenced by DNA methylation and histone deacetylation in non-small cell lung cancer (NSCLC).
  
  
  METHODS
  We used microarray analysis to screen for tumor suppressor genes.
  
  
  RESULTS
  We identified Per1, a core circadian gene, as a candidate tumor suppressor in lung cancer. Although Per1 levels were high in normal lung, its expression was low in a large panel of NSCLC patient samples and cell lines. Forced expression of Per1 in NSCLC cell lines led to significant growth reduction and loss of clonogenic survival. Recent studies showed that epigenetic regulation, particularly histone H3 acetylation, is essential for circadian function. Using bisulfite sequencing and chromatin immunoprecipitation, we found that DNA hypermethylation and histone H3 acetylation are potential mechanisms for silencing Per1 expression NSCLC.
  
  
  CONCLUSIONS
  These results support the hypothesis that disruption of circadian rhythms plays an important role in lung tumorigenesis. Moreover, our findings suggest a novel link between circadian epigenetic regulation and cancer development.
authors.affiliation: Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California 90048, USA. gerys@cshs.org
authors.forename: Sigal
authors.initials: S
authors.lastname: Gery
authors.forename: Naoki
authors.initials: N
authors.lastname: Komatsu
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kawamata
authors.forename: Carl W
authors.initials: CW
authors.lastname: Miller
authors.forename: Julian
authors.initials: J
authors.lastname: Desmond
authors.forename: Renu K
authors.initials: RK
authors.lastname: Virk
authors.forename: Alberto
authors.initials: A
authors.lastname: Marchevsky
authors.forename: Robert
authors.initials: R
authors.lastname: Mckenna
authors.forename: Hirokuni
authors.initials: H
authors.lastname: Taguchi
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002940:Circadian Rhythm / Q000502:physiology*; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D056950:Period Circadian Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018797:Cell Cycle Proteins; C539022:PER1 protein, human; D056950:Period Circadian Proteins