MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor β type II receptor expression in human breast cancer cells

Transcriptional repression of the transforming growth factor (TGF)-beta type II receptor (T beta RII) gene appears to be a major mechanism to inactivate TGF-beta 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 T beta RII mRNA, but not TGF-beta 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 T beta RII promoter after treatment with MS-275, However, the level of histone acetylation did not change in chromatin associated with the TGF-beta type I receptor gene. MS-275 treatment enhanced TGF-beta1-induced plasminogen activator inhibitor 1 expression. Thus, antitumor activity of MS-275 may be mediated in part through the induction of T beta RII expression and consequent potentiation of TGF-beta signaling.