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...

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Published in:Life sciences (1973) 2008-01, Vol.82 (5), p.247-255
Main Authors: Cui, Yi, Lu, Cailing, Liu, Liyong, Sun, Daguang, Yao, Nan, Tan, Sainan, Bai, Shanshan, Ma, Xu
Format: Article
Language:English
Subjects:
Antioxidants - pharmacology
Cell Line, Tumor
Cell Proliferation - drug effects
Cellular Senescence - drug effects
CpG Islands - drug effects
CpG Islands - genetics
Cyclin-Dependent Kinase Inhibitor Proteins - genetics
Cyclin-Dependent Kinase Inhibitor Proteins - metabolism
DNA Methylation - drug effects
Dose-Response Relationship, Drug
Female
G1 Phase - drug effects
Gene Expression Regulation, Neoplastic - drug effects
Gene Silencing - drug effects
Genes, p16 - drug effects
Humans
Lignan
Masoprocol - pharmacology
Methylation
NDGA
p16INK4a
Phytoestrogen
Sequence Analysis, DNA
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Summary: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.
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2007.11.013