© The Author 2006. Published by Oxford University Press.
ARTICLE |
Epigenetic Modulation of Tumor Suppressor CCAAT/Enhancer Binding Protein 
Activity in Lung Cancer
Affiliations of authors: Department of Molecular Virology, Immunology, and Medical Genetics, Division of Human Cancer Genetics (YT, RMB, BH, CP), Department of Pathology (CM), Department of Internal Medicine, Division of Hematology and Oncology (GAO, CP), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Department of Hematology and Oncology, University of Freiburg Medical Center, Freiburg, Germany (BH)
Correspondence to: Christoph Plass, PhD, The Ohio State University, Division of Human Cancer Genetics, Tzagournis Medical Research Facility 464A, 420 West 12th Ave., Columbus, OH 43210 (e-mail: christoph.plass{at}osumc.edu).
Background: Loss of tumor suppressor CCAAT/enhancer-binding protein-
(C/EBP) expression is seen in several human malignancies, including acute myelogenous leukemia and lung cancer. We hypothesized that DNA methylation and histone acetylation of the C/EBP promoter may modulate C/EBP expression in lung cancer. Methods: We analyzed C/EBP expression in 15 human lung cancer cell lines and in 122 human lung primary tumors by northern blotting, immunoblotting, and immunohistochemistry. C/EBP promoter methylation was assessed using bisulfite sequencing, combined bisulfite restriction analysis, methylation-specific polymerase chain reaction, and Southern blotting. We examined the acetylation status of histones H3 and H4 at the C/EBP promoter by chromatin immunoprecipitation. Binding of methyl-CpG–binding proteins MeCP2 and MBD2 and upstream stimulatory factor (USF) to the C/EBP promoter was assayed in cell lines that were untreated or treated with histone deacetylase inhibitor trichostatin A and demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) by chromatin immunoprecipitation and by electrophoretic mobility shift assays. Results: DNA methylation and histone acetylation in the upstream region (–1422 to –896) of the C/EBP promoter were associated with low or absent C/EBP expression in 12 of 15 lung cancer cell lines and in 81 of 120 primary lung tumors. MeCP2 and MBD binding to the upstream C/EBP promoter was detected in C/EBP-nonexpressing cell lines; USF binding was detected in C/EBP-expressing cell lines; however, in C/EBP-nonexpressing cell lines USF binding was detected only after trichostatin A and 5-aza-dC treatment. Conclusions: DNA hypermethylation of the upstream C/EBP promoter region, not the core promoter region as previously reported, is critical in the regulation of C/EBP expression in human lung cancer.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Li, H.-i. H. Paik, C. Balch, Y. Kim, L. Li, T. H-M. Huang, K. P. Nephew, and S. Kim Enriched transcription factor binding sites in hypermethylated gene promoters in drug resistant cancer cells Bioinformatics, August 15, 2008; 24(16): 1745 - 1748. [Abstract] [PDF]
|
|
|
|
 |
|
 G. Huang, R. Eisenberg, M. Yan, S. Monti, E. Lawrence, P. Fu, J. Walbroehl, E. Lowenberg, T. Golub, J. Merchan, et al. 15-Hydroxyprostaglandin Dehydrogenase is a Target of Hepatocyte Nuclear Factor 3{beta} and a Tumor Suppressor in Lung Cancer Cancer Res., July 1, 2008; 68(13): 5040 - 5048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Hackanson, K. L. Bennett, R. M. Brena, J. Jiang, R. Claus, S.-S. Chen, N. Blagitko-Dorfs, K. Maharry, S. P. Whitman, T. D. Schmittgen, et al. Epigenetic Modification of CCAAT/Enhancer Binding Protein {alpha} Expression in Acute Myeloid Leukemia Cancer Res., May 1, 2008; 68(9): 3142 - 3151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Hasemann, I. Damgaard, M. B. Schuster, K. Theilgaard-Monch, A. B. Sorensen, A. Mrsic, T. Krugers, B. Ylstra, F. S. Pedersen, C. Nerlov, et al. Mutation of C/EBP{alpha} predisposes to the development of myeloid leukemia in a retroviral insertional mutagenesis screen Blood, April 15, 2008; 111(8): 4309 - 4321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Yang, Y. Jiang, S.F. Wu, M.Y. Zhou, Y.L. Wu, and G.Q. Chen CCAAT/enhancer-binding protein {alpha} antagonizes transcriptional activity of hypoxia-inducible factor 1 {alpha} with direct protein-protein interaction Carcinogenesis, February 1, 2008; 29(2): 291 - 298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Wouters, M. A. Jorda, K. Keeshan, I. Louwers, C. A. J. Erpelinck-Verschueren, D. Tielemans, A. W. Langerak, Y. He, Y. Yashiro-Ohtani, P. Zhang, et al. Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1 Blood, November 15, 2007; 110(10): 3706 - 3714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C.-l. Lam, L. Girard, R. Ramirez, W.-s. Chau, W.-s. Suen, S. Sheridan, V. P.C. Tin, L.-p. Chung, M. P. Wong, J. W. Shay, et al. Expression of Nicotinic Acetylcholine Receptor Subunit Genes in Non-Small-Cell Lung Cancer Reveals Differences between Smokers and Nonsmokers Cancer Res., May 15, 2007; 67(10): 4638 - 4647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Bennett, B. Hackanson, L. T. Smith, C. D. Morrison, J. C. Lang, D. E. Schuller, F. Weber, C. Eng, and C. Plass Tumor Suppressor Activity of CCAAT/Enhancer Binding Protein {alpha} Is Epigenetically Down-regulated in Head and Neck Squamous Cell Carcinoma Cancer Res., May 15, 2007; 67(10): 4657 - 4664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Agrawal, W.-K. Hofmann, N. Tidow, M. Ehrich, D. v. d. Boom, S. Koschmieder, W. E. Berdel, H. Serve, and C. Muller-Tidow The C/EBP{delta} tumor suppressor is silenced by hypermethylation in acute myeloid leukemia Blood, May 1, 2007; 109(9): 3895 - 3905. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nikitina, X. Shi, R. P. Ghosh, R. A. Horowitz-Scherer, J. C. Hansen, and C. L. Woodcock Multiple Modes of Interaction between the Methylated DNA Binding Protein MeCP2 and Chromatin Mol. Cell. Biol., February 1, 2007; 27(3): 864 - 877. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Yin, J. M. Ong, J. Hu, J. C. Desmond, N. Kawamata, B. M. Konda, K. L. Black, and H. P. Koeffler Suberoylanilide Hydroxamic Acid, a Histone Deacetylase Inhibitor: Effects on Gene Expression and Growth of Glioma Cells In vitro and In vivo Clin. Cancer Res., February 1, 2007; 13(3): 1045 - 1052. [Abstract] [Full Text] [PDF]
|
|