Reactivation of methylation-silenced tumor suppressor gene p16INK4a by nordihydroguaiaretic acid and its implication in G1 cell cycle arrest.
Phytoestrogens, including the two major groups isoflavones and lignans, are chemicals with weak estrogenic activity which occur naturally in many foods and herbs. Recently, several intriguing studies reported that some isoflavones can affect DNA methylation status. However, little is known about the effect of plant lignans on epigenetic modification. Using cultured T47D and RKO human cancer cells as a model, we studied the modulating effects of nordihydroguaiaretic acid (NDGA), a member of the lignan family, on the methylation status of the gene promoter region. Our results indicated that NDGA reverses p16INK4a CpG island hypermethylation, and restores its transcription and expression in both cell lines. Cytometric analysis showed that NDGA significantly affects cell cycle progression by arresting cells at the G1 phase. Consistent with the reacquisition of p16INK4a expression, we also found that NDGA induces cellular senescence in cancer cells. This is the first study demonstrating that a member of the lignan family can induce demethylation in human cancer cell lines, suggesting a novel epigenetic mechanism in the prevention or treatment of cancer.
Cui
Yi
Y
Department of Genetics, Peking Union Medical College, Beijing, 100005, China.
Lu
Cailing
C
Liu
Liyong
L
Sun
Daguang
D
Yao
Nan
N
Tan
Sainan
S
Bai
Shanshan
S
Ma
Xu
X
D000975:Antioxidants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D018899:CpG Islands / Q000187:drug effects / Q000235:genetics; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects*; D019942:Genes, p16 / Q000187:drug effects*; D006801:Humans; D009637:Masoprocol / Q000494:pharmacology*; D017422:Sequence Analysis, DNA
D000975:Antioxidants; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D009637:Masoprocol