Elucidating the Mechanism of Regulation of Transforming Growth Factor β 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 transforming growth factor beta (TGF-beta)-induced tumor suppressor function in tumors plays a pivotal role in this process, and our previous studies have shown that resistance to TGF-beta in lung cancers occurs mostly through the loss of TGF-beta type II receptor expression (T beta RII). However, little is known about the mechanism of down-regulation of T beta RII and how histone deacetylase (HDAC) inhibitors (HDIs) can restore TGF-beta-induced tumor suppressor function. Here we show that HDIs restore T beta RII expression and that DNA hypermethylation has no effect on T beta RII promoter activity in lung cancer cell lines. TGF-beta-induced tumor suppressor function is restored by HDIs in lung cancer cell lines that lack T beta RII expression. Activation of mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by either activated Ras or epidermal growth factor signaling is involved in the down-regulation of T beta RII through histone deacetylation. We have immunoprecipitated the protein complexes by biotinylated oligonucleotides corresponding to the HDI-responsive element in the T beta RII promoter (-127/-75) and identified the proteins/factors using proteomics studies. The transcriptional repressor Meis1/2 is involved in repressing the T beta RII promoter activity, possibly through its recruitment by Sp1 and NF-YA to the promoter. These results suggest a mechanism for the down-regulation of T beta RII in lung cancer and that TGF-beta tumor suppressor functions may be restored by HDIs in lung cancer patients with the loss of T beta RII expression.