This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Velicescu, M. Articles by Jones, P. A. Search for Related Content PubMed PubMed Citation Articles by Velicescu, M. Articles by Jones, P. A.

Cell Division Is Required for de Novo Methylation of CpG Islands in Bladder Cancer Cells¹

Urologic Cancer Research Laboratory, Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, University of Southern California, Keck School of Medicine, Los Angeles, California 90089-9181

Cell division is essential for tumor development and progression. Methylation-mediated silencing caused by aberrant de novo methylation of CpG islands located in the promoter regions of growth regulatory genes occurs frequently in human cancers. We investigated the relationship between cell division and de novo methylation to determine whether de novo methylation can occur in the absence of cell division in cancer cells. We treated T24 bladder carcinoma cells with 5-Aza-2'-deoxycytidine to induce a transient demethylation and then compared the timing and kinetics of remethylation of the p16 gene locus under conditions of either G₀-G₁ growth arrest induced by serum starvation and confluence or continuous cell proliferation in complete medium. Variable levels of remethylation were detected in CpG poor regions of DNA, as well as repetitive DNA elements in the absence of cell division, yet no remethylation occurred at CpG islands under these conditions. This correlated with continuous expression of p16 protein in these cells. DNA methyltransferase (DNMT)1 and DNMT3b3 proteins were undetectable in 5-Aza-2'-deoxycytidine-treated and untreated nondividing cells, and their mRNA transcripts were down-regulated in these cells. Although DNMT3a mRNA levels were also reduced, they recovered to original levels in nondividing cells after drug treatment. Our results suggest that cell division is required for de novo methylation of CpG islands and that DNMT3a may play a role in methylating CpG poor regions or repetitive DNA elements outside of the S phase of the cell cycle.

This article has been cited by other articles:

				K. D. Siegmund, P. Marjoram, Y.-J. Woo, S. Tavare, and D. Shibata Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers PNAS, March 24, 2009; 106(12): 4828 - 4833. [Abstract] [Full Text] [PDF]

				L.-P. Wu, X. Wang, L. Li, Y. Zhao, S. Lu, Y. Yu, W. Zhou, X. Liu, J. Yang, Z. Zheng, et al. Histone Deacetylase Inhibitor Depsipeptide Activates Silenced Genes through Decreasing both CpG and H3K9 Methylation on the Promoter Mol. Cell. Biol., May 15, 2008; 28(10): 3219 - 3235. [Abstract] [Full Text] [PDF]

				I. Zighelboim, P. J. Goodfellow, A. P. Schmidt, K. C. Walls, M. A. Mallon, D. G. Mutch, P. S. Yan, T. H.-M. Huang, and M. A. Powell Differential Methylation Hybridization Array of Endometrial Cancers Reveals Two Novel Cancer-Specific Methylation Markers Clin. Cancer Res., May 15, 2007; 13(10): 2882 - 2889. [Abstract] [Full Text] [PDF]

				J. Tan, X. Yang, L. Zhuang, X. Jiang, W. Chen, P. L. Lee, R.K. M. Karuturi, P. B. O. Tan, E. T. Liu, and Q. Yu Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells Genes & Dev., May 1, 2007; 21(9): 1050 - 1063. [Abstract] [Full Text] [PDF]

				Z. Herceg Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors Mutagenesis, March 1, 2007; 22(2): 91 - 103. [Abstract] [Full Text] [PDF]

				T. Maekita, K. Nakazawa, M. Mihara, T. Nakajima, K. Yanaoka, M. Iguchi, K. Arii, A. Kaneda, T. Tsukamoto, M. Tatematsu, et al. High Levels of Aberrant DNA Methylation in Helicobacter pylori-Infected Gastric Mucosae and its Possible Association with Gastric Cancer Risk Clin. Cancer Res., February 1, 2006; 12(3): 989 - 995. [Abstract] [Full Text] [PDF]

				F. Lyko and R. Brown DNA Methyltransferase Inhibitors and the Development of Epigenetic Cancer Therapies J Natl Cancer Inst, October 19, 2005; 97(20): 1498 - 1506. [Abstract] [Full Text] [PDF]

				Q. Zhang, J. N. Rubenstein, T. L. Jang, M. Pins, B. Javonovic, X. Yang, S.-J. Kim, I. Park, and C. Lee Insensitivity to Transforming Growth Factor-{beta} Results from Promoter Methylation of Cognate Receptors in Human Prostate Cancer Cells (LNCaP) Mol. Endocrinol., September 1, 2005; 19(9): 2390 - 2399. [Abstract] [Full Text] [PDF]

				C. Pantoja, L. de los Rios, A. Matheu, F. Antequera, and M. Serrano Inactivation of Imprinted Genes Induced by Cellular Stress and Tumorigenesis Cancer Res., January 1, 2005; 65(1): 26 - 33. [Abstract] [Full Text] [PDF]

				A. H. Lund and M. van Lohuizen Epigenetics and cancer Genes & Dev., October 1, 2004; 18(19): 2315 - 2335. [Abstract] [Full Text] [PDF]

				M. Suzuki, N. Sunaga, D. S. Shames, S. Toyooka, A. F. Gazdar, and J. D. Minna RNA Interference-Mediated Knockdown of DNA Methyltransferase 1 Leads to Promoter Demethylation and Gene Re-Expression in Human Lung and Breast Cancer Cells Cancer Res., May 1, 2004; 64(9): 3137 - 3143. [Abstract] [Full Text] [PDF]

				J. C. Cheng, D. J. Weisenberger, F. A. Gonzales, G. Liang, G.-L. Xu, Y.-G. Hu, V. E. Marquez, and P. A. Jones Continuous Zebularine Treatment Effectively Sustains Demethylation in Human Bladder Cancer Cells Mol. Cell. Biol., February 1, 2004; 24(3): 1270 - 1278. [Abstract] [Full Text] [PDF]

				D. J. Weisenberger, M. Velicescu, J. C. Cheng, F. A. Gonzales, G. Liang, and P. A. Jones Role of the DNA Methyltransferase Variant DNMT3b3 in DNA Methylation Mol. Cancer Res., January 1, 2004; 2(1): 62 - 72. [Abstract] [Full Text] [PDF]

				J.-P. J. Issa Methylation and Prognosis: Of Molecular Clocks and Hypermethylator Phenotypes Clin. Cancer Res., August 1, 2003; 9(8): 2879 - 2881. [Full Text] [PDF]

				H. S. Judelson and S. Roberts Novel Protein Kinase Induced during Sporangial Cleavage in the Oomycete Phytophthora infestans Eukaryot. Cell, October 1, 2002; 1(5): 687 - 695. [Abstract] [Full Text] [PDF]