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

Weiqi Huang, Shujie Zhao, Sudhakar Ammanamanchi, Michael Brattain, Kolaparthi Venkatasubbarao, James W Freeman
Journal of Biological Chemistry 2005 March 18, 280 (11): 10047-54
Transforming growth factor beta type II receptor (TbetaRII) 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 TbetaRII in human pancreatic cancer cell lines by modulating the transcriptional components that bind a specific DNA region of the TbetaRII promoter. This region of the TbetaRII promoter possesses Sp1 and NF-Y binding sites in close proximity (located at -102 and -83, respectively). Treatment of cells with TSA activates the TbetaRII 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 TbetaRII 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 TbetaRII mRNA expression, the association of PCAF with TbetaRII promoter, and the acetylation of Sp1. Taken together, these results showed that TSA treatment of pancreatic cancer cells leads to transcriptional activation of the TbetaRII 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.

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