S. Milutinovic et al., DNA methyltransferase inhibition induces the transcription of the tumor suppressor p21(WAF1/CIP1/sdi1), J BIOL CHEM, 275(9), 2000, pp. 6353-6359
Previous lines of evidence have shown that inhibition of DNA methyltransfer
ase (MeTase) can arrest tumor cell growth; however, the mechanisms involved
were not clear, In this manuscript we show that out of 16 known tumor supp
ressors and cell cycle regulators, the cyclin-dependent kinase inhibitor p2
1 is the only tumor suppressor induced in the human lung cancer cell line,
A549, following inhibition of DNA MeTase by a novel DNA MeTase antagonist o
r antisense oligonucleotides. The rapid induction of p21 expression points
to a mechanism that does not involve demethylation of p21 promoter. Consist
ent with this hypothesis, we show that part of the CpG island upstream of t
he endogenous p21 gene is unmethylated and that the expression of unmethyla
ted p21 promoter luciferase reporter constructs is induced following inhibi
tion of DNA MeTase. These results are consistent with the hypothesis that t
he level of DNA MeTase in a cell can control the expression of a nodal tumo
r suppressor by a mechanism that does not involve DNA methylation.