MS-275, A Histone Deacetylase Inhibitor, Selectively Induces Transforming Growth Factor β Type II Receptor Expression in Human Breast Cancer Cells
2001
Transcriptional repression of the transforming growth factor (TGF)-β
type II receptor ( Tβ RII ) gene
appears to be a major mechanism to inactivate TGF-β responsiveness in
many human cancers. Because histone acetylation/deacetylation plays a
role in transcriptional regulation, we have examined the effect of
MS-275, a synthetic inhibitor of histone deacetylase, in human breast
cancer cell lines. MS-275 showed antiproliferative activity against all
human breast cancer cell lines examined and induced TβRII mRNA, but
not TGF-β type I receptor mRNA. MS-275 caused an accumulation of
acetylated histones H3 and H4 in total cellular chromatin. An increase
in the accumulation of acetylated histones H3 and H4 was detected in
the TβRII promoter after treatment with MS-275. However, the level of
histone acetylation did not change in chromatin associated with the
TGF-β type I receptor gene. MS-275 treatment enhanced
TGF-β1-induced plasminogen activator inhibitor 1 expression. Thus,
antitumor activity of MS-275 may be mediated in part through the
induction of TβRII expression and consequent potentiation
of TGF-β signaling.
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