Trichostatin a induces transforming growth factor ß type II receptor promoter activity and acetylation of Sp1 by recruitment of PCAF/p300 to a Sp1•NF-Y complex

Transforming growth factor beta type II receptor (T beta RII) is a tumor suppressor gene that can be transcriptionally silenced by histone deacetylases (HDACs) in cancer cells. In this report, we demonstrated the mechanism by which trichostatin A (TSA), an inhibitor of HDAC, induces the expression of T beta RII in human pancreatic cancer cell lines by modulating the transcriptional components that bind a specific DNA region of the T beta RII promoter. This region of the T beta RII promoter possesses Sp1 and NF-Y binding sites in close proximity ( located at -102 and -83, respectively). Treatment of cells with TSA activates the T beta RII promoter in a time-dependent manner through the recruitment of p300 and PCAF into a Sp1(.)NF-Y(.)HDAC complex that binds this DNA element. The recruitment of p300 and PCAF into the complex is associated with a concomitant acetylation of Sp1 and an overall decrease in the amount of HDAC associated with the complex. Transient overexpression of p300 or PCAF potentiated TSA-induced T beta RII promoter activity. The effect of PCAF was dependent on its histone acetyltransferase activity, whereas that of p300 was independent. Stable transfection of PCAF caused an increase in T beta RII mRNA expression, the association of PCAF with T beta RII promoter, and the acetylation of Sp1. Taken together, these results showed that TSA treatment of pancreatic cancer cells leads to transcriptional activation of the T beta RII promoter through modulation of the components of a Sp1(.)NF-Y(.)p300(.)PCAF(.)HDAC-1 multiprotein complex. Moreover, the interaction of NF-Y with the Sp1-associated complex may further explain why this specific Sp1 site mediates transcriptional responsiveness to TSA.