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Tumor Biology |
Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
Transforming growth factor (TGF)-ß strongly inhibits epithelial cell proliferation. Alterations of TGF-ß signaling are thought to play a role in tumorigenesis. We show in the present study that most lung cancer cell lines have lost the growth-inhibitory response to TGF-ß signal, and that those with TGF-ß unresponsiveness can be divided into two major groups, TGF-ß type II receptor (TGFßRII)(+)/Smad7(+) and TGFßRII(-)/Smad7(-), suggesting the heterogeneous mechanisms underlying the TGF-ß responsiveness. The mechanism of the loss of TGFßRII expression of the latter group was further studied, identifying aberrant DNA methylation of the promoter region in a limited fraction of cell lines. Interestingly, we found that the alteration of chromatin structure because of histone deacetylation may also be involved, showing a good correlation with loss of TGFßRII expression. This notion was supported by the findings of a restriction enzyme accessibility assay, of a chromatin immunoprecipitation assay with anti-acetyl histone antibodies, and of an in vivo induction of TGFßRII expression by histone deacetylase inhibitors including trichostatin A (TSA) and sodium butyrate. In vitro induction of TGFßRII promoter reporter activity by TSA was also detected and found to require the CCAAT box within the -127/-75 region. A positive regulatory mechanism for TGFßRII expression in a TGF-ß-expressing cell line was also investigated, and a TPA-responsive element (TRE)-like motif, TRE2, was detected in addition to the previously reported TRE-like motif Y element in the positive regulatory region. Alterations in two discrete proteins interacting with these two TRE-like motifs were also suspected of being involved in the loss of TGFßRII expression. This is the first study to demonstrate that, in addition to the TSA-responsive region and TRE2 motif in the TGFßRII promoter, the alteration of histone deacetylation may be involved in the loss of TGFßRII expression in lung cancer cell lines.
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