Epigenetic silencing of the candidate tumor suppressor gene Per1 in non-small cell lung cancer.
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.
Gery
Sigal
S
Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California 90048, USA. gerys@cshs.org
Komatsu
Naoki
N
Kawamata
Norihiko
N
Miller
Carl W
CW
Desmond
Julian
J
Virk
Renu K
RK
Marchevsky
Alberto
A
Mckenna
Robert
R
Taguchi
Hirokuni
H
Koeffler
H Phillip
HP
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
D018797:Cell Cycle Proteins; C539022:PER1 protein, human; D056950:Period Circadian Proteins