Elucidating the mechanism of regulation of transforming growth factor β type II receptor expression in human lung cancer cell lines

Sunil K. Halder, Yong Jig Cho, Arunima Datta, Govindaraj Anumanthan, Amy Joan L. Ham, David P. Carbone, Pran K. Datta

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)912-922
Number of pages11
JournalNeoplasia
Volume13
Issue number10
DOIs
StatePublished - Oct 2011

ASJC Scopus subject areas

  • Cancer Research

Fingerprint Dive into the research topics of 'Elucidating the mechanism of regulation of transforming growth factor β type II receptor expression in human lung cancer cell lines'. Together they form a unique fingerprint.

  • Cite this

    Halder, S. K., Cho, Y. J., Datta, A., Anumanthan, G., Ham, A. J. L., Carbone, D. P., & Datta, P. K. (2011). Elucidating the mechanism of regulation of transforming growth factor β type II receptor expression in human lung cancer cell lines. Neoplasia, 13(10), 912-922. https://doi.org/10.1593/neo.11576