Elucidating the mechanism of regulation of TGF- type II receptor expression in human lung cancer cell lines

Lung carcinogenesis in humans involves an accumulation of genetic and epigenetic changes that lead to alterations in normal lung epithelium, to in situ carcinoma, and finally to invasive and metastatic cancers. The loss of TGF--induced tumor suppressor function in tumors plays a pivotal role in this process, and our previous studies have shown that resistance to TGF- in lung cancers occurs mostly through the loss of TGF- type II (TRII) receptor expression. However, little is known about the mechanism of down-regulation of TRII and how HDAC inhibitors (HDI) can restore TGF--induced tumor suppressor function. Here we show that HDAC inhibitors restore TRII expression and that DNA hypermethylation has no effect on TRII promoter activity in lung cancer cell lines. TGF--induced tumor suppressor function is restored by HDAC inhibitors in lung cancer cell lines that lack TRII expression. Activation of MAPK/ERK pathway by either activated Ras or EGF signaling is involved in the down-regulation of TRII through histone deacetylation. We have immunoprecipitated the protein complexes by biotinylated oligonucleotides corresponding to HDI responsive element in TRII promoter (-127/-75) and identified the proteins/factors using proteomics studies. The transcriptional repressor Meis1/2 is involved in repressing the TRII promoter activity, possibly through its recruitment by Sp1 and NF-YA to the promoter. These results suggest a mechanism for the down-regulation of TRII in lung cancer and that TGF- tumor suppressor functions may be restored by HDAC inhibitors in lung cancer patients with loss of TRII expression.