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

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

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 - Jan 1 2011

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Growth Factor Receptors
Transforming Growth Factors
Histone Deacetylase Inhibitors
Lung Neoplasms
Cell Line
Neoplasms
Down-Regulation
Lung
Extracellular Signal-Regulated MAP Kinases
Carcinoma in Situ
Mitogen-Activated Protein Kinases
Epidermal Growth Factor
Epigenomics
Oligonucleotides
Proteomics
Histones
Carcinogenesis
Proteins
Epithelium
DNA

ASJC Scopus subject areas

  • Cancer Research

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

Elucidating the mechanism of regulation of transforming growth factor β type II receptor expression in human lung cancer cell lines. / Halder, Sunil Krishna; Cho, Yong Jig; Datta, Arunima; Anumanthan, Govindaraj; Ham, Amy Joan L.; Carbone, David P.; Datta, Pran K.

In: Neoplasia, Vol. 13, No. 10, 01.01.2011, p. 912-922.

Research output: Contribution to journalArticle

Halder, SK, Cho, YJ, Datta, A, Anumanthan, G, Ham, AJL, Carbone, DP & Datta, PK 2011, 'Elucidating the mechanism of regulation of transforming growth factor β type II receptor expression in human lung cancer cell lines', Neoplasia, vol. 13, no. 10, pp. 912-922. https://doi.org/10.1593/neo.11576
Halder, Sunil Krishna ; Cho, Yong Jig ; Datta, Arunima ; Anumanthan, Govindaraj ; Ham, Amy Joan L. ; Carbone, David P. ; Datta, Pran K. / Elucidating the mechanism of regulation of transforming growth factor β type II receptor expression in human lung cancer cell lines. In: Neoplasia. 2011 ; Vol. 13, No. 10. pp. 912-922.
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