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Molecular Biology and Genetics |
/Signal Transducers and Activators of Transcription (STAT) Pathway by Hypermethylation at a STAT-binding Site in the p21WAF1 Promoter Region1
Department of Pathology, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, Arkansas 72202 [B. C., L. H., V. H. S., D. M. P.], and Department of Pathology and Laboratory Medicine, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 [J. J. J.]
Expression of the cyclin-dependent kinase inhibitor
p21WAF1 can be up-regulated by activation
of signal transducers and activators of transcription (STAT) proteins
in response to IFN-
. In this study, we examined CpG methylation at
the p21WAF1 promoter region in rhabdomyosarcomas
(RMSs) using Southern blot analysis with the
methylation-sensitive restriction enzyme HpaII.
Sis-inducible element (SIE)-1, a STAT-responsive element located
upstream of the p21WAF1 CpG island, was
completely methylated at an internal CpG in 13 of 26 (50%) primary RMS
tumors and 2 of 5 RMS cell lines. In contrast, all normal tissues
examined showed a partial methylation pattern at SIE-1. Complete
methylation within SIE-1 strongly correlated with decreased
p21WAF1 mRNA expression in RMS. We further
studied the effects of SIE-1 hypermethylation on
p21WAF1 induction by STAT activation. CpG
methylation within SIE-1 significantly inhibited binding of activated
STAT1 in electrophoretic mobility shift assays and abrogated
STAT-mediated transcription activation in response to IFN- in
luciferase reporter gene assays. Activation of STAT1 in response to
IFN- resulted in increased p21WAF1 expression
and growth suppression in RMS cells containing unmethylated SIE-1 but
failed to induce p21WAF1 or growth inhibition in
RD and A673 cells, both of which were completely methylated within
SIE-1. However, demethylation at SIE-1, induced by a demethylating
agent 5-aza-2'-deoxycytidine, reactivated
p21WAF1 expression and restored the
responsiveness to IFN- in RD cells. Our results indicate a mechanism
by which altered DNA methylation in the p21WAF1
promoter region, by precluding STAT1 binding to SIE-1, directly
inhibits the p21WAF1 induction and cell growth
regulation through the IFN-/STAT signaling pathway in RMS cells.
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