Transcriptional regulation of the transforming growth factor beta type II receptor gene by histone acetyltransferase and deacetylase is mediated by NF-Y in human breast cancer cells

Seok Hee Park, Sae Ra Lee, Byung Chul Kim, Eun Ah Cho, Sejal P Patel, Hee-Bum Kang, Edward A Sausville, Osamu Nakanishi, Jane B Trepel, Byoung Ick Lee, Seong-Jin Kim
Journal of Biological Chemistry 2002 February 15, 277 (7): 5168-74
Transcriptional repression of the transforming growth factor-beta (TGF-beta) type II receptor (TbetaRII) gene is one of several mechanisms leading to TGF-beta resistance. Previously, we have shown that MS-275, a synthetic inhibitor of histone deacetylase (HDAC), specifically induces the expression of the TbetaRII gene and restores the TGF-beta signaling in human breast cancer cell lines. However, little is known about the mechanism by which inhibition of HDAC activates TbetaRII expression. MS-275 treatment of cells expressing a wild-type TbetaRII promoter/luciferase construct resulted in a 10-fold induction of the promoter activity. DNA transfection and an electrophoretic mobility shift assay showed that the induction of the TbetaRII promoter by MS-275 requires the inverted CCAAT box and its cognate binding protein, NF-Y. In addition, a DNA affinity pull-down assay indicated that the PCAF protein, a transcriptional coactivator with intrinsic histone acetyltransferase (HAT) activity, is specifically recruited to the NF-Y complex in the presence of either MS-275 or trichostatin A. Based on these results, we suggest that treatment with the HDAC inhibitor induces TbetaRII promoter activity by the recruitment of the PCAF protein to the NF-Y complex, interacting with the inverted CCAAT box in the TbetaRII promoter.

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