QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Karpf, A. R. Articles by Jones, D. A. Search for Related Content PubMed PubMed Citation Articles by Karpf, A. R. Articles by Jones, D. A.

Limited Gene Activation in Tumor and Normal Epithelial Cells Treated with the DNA Methyltransferase Inhibitor 5-Aza-2'-deoxycytidine

Huntsman Cancer Institute (A.R.K., T.O.R., A.N.K., D.G., D.A.J.) and the Departments of Oncological Sciences (A.R.K., D.G., D.A.J.) and Dermatology (D.G.), University of Utah, Salt Lake City, Utah; and Incyte Corporation, Palo Alto, California (A.W.L.)

It remains unclear to what extent drugs targeting transcriptional repressor complexes affect global gene expression in cells derived from target and nontarget human tissues. To address this question, we used genome-wide expression analysis using microarrays to analyze the response of three tumor and one normal epithelial cell line to treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR). Notably, we found that 5-aza-CdR treatment induced a limited number of genes (mean, 0.67%; range, 0.17-1.8% of 25,940 genes screened) in each cell line tested. The majority of the gene expression changes that followed 5-aza-CdR treatment were conserved in tumor and normal cells, including genes that function in cell proliferation, differentiation, immune presentation, and cytokine signaling. In contrast, 5-aza-CdR treatment induced the expression of cancer-testis class tumor antigens only in tumor cell lines. To explain this tissue-specific response, we analyzed the mechanism of transcriptional regulation of the prototype member of this tumor antigen gene family, MAGE-1. Taken from our analysis of MAGE-1 gene regulation, we propose that 5-aza-CdR-mediated gene activation has two distinct requirements: 1) the reversal of promoter hypermethylation, and 2) the presence of transcriptional activators competent for the activation of hypomethylated target promoters. This latter requirement for gene activation by 5-aza-CdR is probably mediated by sequence-specific transcription factors and may account for the limited number of human genes induced by 5-aza-CdR treatment. This revised model for gene activation by 5-aza-CdR has important implications for the use of DNA methyltransferase inhibitors in clinical settings.

Address correspondence to: David A. Jones, 2000 Circle of Hope, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112. E-mail: david.jones{at}hci.utah.edu

This article has been cited by other articles:

				A. Woloszynska-Read, P. Mhawech-Fauceglia, J. Yu, K. Odunsi, and A. R. Karpf Intertumor and Intratumor NY-ESO-1 Expression Heterogeneity Is Associated with Promoter-Specific and Global DNA Methylation Status in Ovarian Cancer Clin. Cancer Res., June 1, 2008; 14(11): 3283 - 3290. [Abstract] [Full Text] [PDF]

				T. Ripperger, N. von Neuhoff, K. Kamphues, M. Emura, U. Lehmann, M. Tauscher, M. Schraders, P. Groenen, B. Skawran, C. Rudolph, et al. Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle cell lymphomas Haematologica, April 1, 2007; 92(4): 460 - 468. [Abstract] [Full Text] [PDF]

				J. Xu, J.-Y. Zhou, M. A. Tainsky, and G. S. Wu Evidence that Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Induction by 5-Aza-2'-Deoxycytidine Sensitizes Human Breast Cancer Cells to Adriamycin Cancer Res., February 1, 2007; 67(3): 1203 - 1211. [Abstract] [Full Text] [PDF]

				T.-Y. Kim, S. Zhong, C. R. Fields, J. H. Kim, and K. D. Robertson Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma. Cancer Res., August 1, 2006; 66(15): 7490 - 7501. [Abstract] [Full Text] [PDF]

				T. Peikert, U. Specks, C. Farver, S. C. Erzurum, and S. A.A. Comhair Melanoma Antigen A4 Is Expressed in Non-Small Cell Lung Cancers and Promotes Apoptosis. Cancer Res., May 1, 2006; 66(9): 4693 - 4700. [Abstract] [Full Text] [PDF]

				F. Wischnewski, K. Pantel, and H. Schwarzenbach Promoter Demethylation and Histone Acetylation Mediate Gene Expression of MAGE-A1, -A2, -A3, and -A12 in Human Cancer Cells Mol. Cancer Res., May 1, 2006; 4(5): 339 - 349. [Abstract] [Full Text] [PDF]

				W. M. Gallagher, O. E. Bergin, M. Rafferty, Z. D. Kelly, I.-M. Nolan, E. J.P. Fox, A. C. Culhane, L. McArdle, M. F. Fraga, L. Hughes, et al. Multiple markers for melanoma progression regulated by DNA methylation: insights from transcriptomic studies Carcinogenesis, November 1, 2005; 26(11): 1856 - 1867. [Abstract] [Full Text] [PDF]

				S. Vatolin, Z. Abdullaev, S. D. Pack, P. T. Flanagan, M. Custer, D. I. Loukinov, E. Pugacheva, J. A. Hong, H. Morse III, D. S. Schrump, et al. Conditional Expression of the CTCF-Paralogous Transcriptional Factor BORIS in Normal Cells Results in Demethylation and Derepression of MAGE-A1 and Reactivation of Other Cancer-Testis Genes Cancer Res., September 1, 2005; 65(17): 7751 - 7762. [Abstract] [Full Text] [PDF]

				R. Schneider-Stock, M. Diab-Assef, A. Rohrbeck, C. Foltzer-Jourdainne, C. Boltze, R. Hartig, P. Schonfeld, A. Roessner, and H. Gali-Muhtasib 5-aza-Cytidine Is a Potent Inhibitor of DNA Methyltransferase 3a and Induces Apoptosis in HCT-116 Colon Cancer Cells via Gadd45- and p53-Dependent Mechanisms J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 525 - 536. [Abstract] [Full Text] [PDF]

				K. Hoek, D. L. Rimm, K. R. Williams, H. Zhao, S. Ariyan, A. Lin, H. M. Kluger, A. J. Berger, E. Cheng, E. S. Trombetta, et al. Expression Profiling Reveals Novel Pathways in the Transformation of Melanocytes to Melanomas Cancer Res., August 1, 2004; 64(15): 5270 - 5282. [Abstract] [Full Text] [PDF]