This Article Full Text Full Text (PDF) Alert me when this article is cited 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 Eads, C. A. Articles by Laird, P. W. Search for Related Content PubMed PubMed Citation Articles by Eads, C. A. Articles by Laird, P. W.

Complete Genetic Suppression of Polyp Formation and Reduction of CpG-Island Hypermethylation in Apc^Min/+ Dnmt1-Hypomorphic Mice¹

Departments of Biochemistry and Molecular Biology [C. A. E., P. W. L.] and Surgery [A. E. N., P. W. L.], University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Room 6418, Los Angeles, California 90089-9176

Promoter CpG island hypermethylation of critical genes is thought to play an important role in human colorectal tumorigenesis. In this study, we show that low levels of CpG island methylation occur in the normal intestinal mucosa of Apc^Min/+ mice and are increased in Multiple Intestinal Metaplasia (Min) polyps. We examined the interaction between CpG island hypermethylation and tumorigenesis by genetically modulating expression levels of the predominant DNA methyltransferase, Dnmt1, in Apc^Min/+ mice. We show that a combination of Dnmt1 hypomorphic alleles results in the complete suppression of polyp formation and an accompanying reduction in the frequency of CpG island methylation in both the normal intestinal mucosa and intestinal adenomas. These results suggest that sufficient DNA methyltransferase expression is a prerequisite for polyp formation and that hypomorphic alleles of Dnmt1 are not merely genetic modifiers but the first identified true genetic suppressors of the Min phenotype.

This article has been cited by other articles:

				N. Shivapurkar, V. Stastny, Y. Xie, C. Prinsen, E. Frenkel, B. Czerniak, F. B. Thunnissen, J. D. Minna, and A. F. Gazdar Differential Methylation of a Short CpG-Rich Sequence within Exon 1 of TCF21 Gene: A Promising Cancer Biomarker Assay Cancer Epidemiol. Biomarkers Prev., April 1, 2008; 17(4): 995 - 1000. [Abstract] [Full Text] [PDF]

				Z. Liu, S.-W. Choi, J. W. Crott, M. K. Keyes, H. Jang, D. E. Smith, M. Kim, P. W. Laird, R. Bronson, and J. B. Mason Mild Depletion of Dietary Folate Combined with Other B Vitamins Alters Multiple Components of the Wnt Pathway in Mouse Colon J. Nutr., December 1, 2007; 137(12): 2701 - 2708. [Abstract] [Full Text] [PDF]

				A. Gregorieff and H. Clevers Giving APCmin tumours a SPARC Gut, October 1, 2007; 56(10): 1341 - 1343. [Full Text] [PDF]

				A. T. Agoston, P. Argani, A. M. De Marzo, J. L. Hicks, and W. G. Nelson Retinoblastoma Pathway Dysregulation Causes DNA Methyltransferase 1 Overexpression in Cancer via MAD2-Mediated Inhibition of the Anaphase-Promoting Complex Am. J. Pathol., May 1, 2007; 170(5): 1585 - 1593. [Abstract] [Full Text] [PDF]

				A. Miremadi, M. Z. Oestergaard, P. D.P. Pharoah, and C. Caldas Cancer genetics of epigenetic genes Hum. Mol. Genet., April 15, 2007; 16(R1): R28 - R49. [Abstract] [Full Text] [PDF]

				V. Muthusamy, S. Duraisamy, C. M. Bradbury, C. Hobbs, D. P. Curley, B. Nelson, and M. Bosenberg Epigenetic Silencing of Novel Tumor Suppressors in Malignant Melanoma Cancer Res., December 1, 2006; 66(23): 11187 - 11193. [Abstract] [Full Text] [PDF]

				H. Lin, Y. Yamada, S. Nguyen, H. Linhart, L. Jackson-Grusby, A. Meissner, K. Meletis, G. Lo, and R. Jaenisch Suppression of Intestinal Neoplasia by Deletion of Dnmt3b Mol. Cell. Biol., April 15, 2006; 26(8): 2976 - 2983. [Abstract] [Full Text] [PDF]

				D. Ray, A. Wu, J. E. Wilkinson, H. S. Murphy, Q. Lu, B. Kluve-Beckerman, J. J. Liepnieks, M. Benson, R. Yung, and B. Richardson Aging in heterozygous dnmt1-deficient mice: effects on survival, the DNA methylation genes, and the development of amyloidosis. J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2006; 61(2): 115 - 124. [Abstract] [Full Text] [PDF]

				A. Prokhortchouk, O. Sansom, J. Selfridge, I. M. Caballero, S. Salozhin, D. Aithozhina, L. Cerchietti, F. G. Meng, L. H. Augenlicht, J. M. Mariadason, et al. Kaiso-Deficient Mice Show Resistance to Intestinal Cancer Mol. Cell. Biol., January 1, 2006; 26(1): 199 - 208. [Abstract] [Full Text] [PDF]

				M. T. McCabe, J. A. Low, S. Daignault, M. J. Imperiale, K. J. Wojno, and M. L. Day Inhibition of DNA Methyltransferase Activity Prevents Tumorigenesis in a Mouse Model of Prostate Cancer Cancer Res., January 1, 2006; 66(1): 385 - 392. [Abstract] [Full Text] [PDF]

				A. Kaneda and A. P. Feinberg Loss of Imprinting of IGF2: A Common Epigenetic Modifier of Intestinal Tumor Risk Cancer Res., December 15, 2005; 65(24): 11236 - 11240. [Abstract] [Full Text] [PDF]

				B. H. Lee, S. Yegnasubramanian, X. Lin, and W. G. Nelson Procainamide Is a Specific Inhibitor of DNA Methyltransferase 1 J. Biol. Chem., December 9, 2005; 280(49): 40749 - 40756. [Abstract] [Full Text] [PDF]

				S. R. Payne and C. J. Kemp Tumor suppressor genetics Carcinogenesis, December 1, 2005; 26(12): 2031 - 2045. [Abstract] [Full Text] [PDF]

				W. J. Lee, J.-Y. Shim, and B. T. Zhu Mechanisms for the Inhibition of DNA Methyltransferases by Tea Catechins and Bioflavonoids Mol. Pharmacol., October 1, 2005; 68(4): 1018 - 1030. [Abstract] [Full Text] [PDF]

				Y. Yamada, L. Jackson-Grusby, H. Linhart, A. Meissner, A. Eden, H. Lin, and R. Jaenisch Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis PNAS, September 20, 2005; 102(38): 13580 - 13585. [Abstract] [Full Text] [PDF]

				J. M. Tucker, J. T. Murphy, N. Kisiel, P. Diegelman, K. W. Barbour, C. Davis, M. Medda, L. Alhonen, J. Janne, D. L. Kramer, et al. Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase Cancer Res., June 15, 2005; 65(12): 5390 - 5398. [Abstract] [Full Text] [PDF]

				A. M. Melnick, K. Adelson, and J. D. Licht The Theoretical Basis of Transcriptional Therapy of Cancer: Can It Be Put Into Practice? J. Clin. Oncol., June 10, 2005; 23(17): 3957 - 3970. [Abstract] [Full Text] [PDF]

				A. T. Agoston, P. Argani, S. Yegnasubramanian, A. M. De Marzo, M. A. Ansari-Lari, J. L. Hicks, N. E. Davidson, and W. G. Nelson Increased Protein Stability Causes DNA Methyltransferase 1 Dysregulation in Breast Cancer J. Biol. Chem., May 6, 2005; 280(18): 18302 - 18310. [Abstract] [Full Text] [PDF]

				M. T. McCabe, J. N. Davis, and M. L. Day Regulation of DNA Methyltransferase 1 by the pRb/E2F1 Pathway Cancer Res., May 1, 2005; 65(9): 3624 - 3632. [Abstract] [Full Text] [PDF]

				P. W. Laird Cancer epigenetics Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R65 - R76. [Abstract] [Full Text] [PDF]

				R. L. Ward, R. Williams, M. Law, and N. J. Hawkins The CpG Island Methylator Phenotype Is Not Associated with a Personal or Family History of Cancer Cancer Res., October 15, 2004; 64(20): 7618 - 7621. [Abstract] [Full Text] [PDF]

				J. Gilbert, S. D. Gore, J. G. Herman, and M. A. Carducci The Clinical Application of Targeting Cancer through Histone Acetylation and Hypomethylation Clin. Cancer Res., July 15, 2004; 10(14): 4589 - 4596. [Abstract] [Full Text] [PDF]

				S. Yegnasubramanian, J. Kowalski, M. L. Gonzalgo, M. Zahurak, S. Piantadosi, P. C. Walsh, G. S. Bova, A. M. De Marzo, W. B. Isaacs, and W. G. Nelson Hypermethylation of CpG Islands in Primary and Metastatic Human Prostate Cancer Cancer Res., March 15, 2004; 64(6): 1975 - 1986. [Abstract] [Full Text] [PDF]

				A. R. Karpf, A. W. Lasek, T. O. Ririe, A. N. Hanks, D. Grossman, and D. A. Jones Limited Gene Activation in Tumor and Normal Epithelial Cells Treated with the DNA Methyltransferase Inhibitor 5-Aza-2'-deoxycytidine Mol. Pharmacol., January 1, 2004; 65(1): 18 - 27. [Abstract] [Full Text] [PDF]

				L. Kopelovich, J. A. Crowell, and J. R. Fay The Epigenome as a Target for Cancer Chemoprevention J Natl Cancer Inst, December 3, 2003; 95(23): 1747 - 1757. [Abstract] [Full Text] [PDF]

				J. G. Herman and S. B. Baylin Gene Silencing in Cancer in Association with Promoter Hypermethylation N. Engl. J. Med., November 20, 2003; 349(21): 2042 - 2054. [Full Text] [PDF]

				M. Z. Fang, Y. Wang, N. Ai, Z. Hou, Y. Sun, H. Lu, W. Welsh, and C. S. Yang Tea Polyphenol (-)-Epigallocatechin-3-Gallate Inhibits DNA Methyltransferase and Reactivates Methylation-Silenced Genes in Cancer Cell Lines Cancer Res., November 15, 2003; 63(22): 7563 - 7570. [Abstract] [Full Text] [PDF]

				S. A. Belinsky, D. M. Klinge, C. A. Stidley, J.-P. Issa, J. G. Herman, T. H. March, and S. B. Baylin Inhibition of DNA Methylation and Histone Deacetylation Prevents Murine Lung Cancer Cancer Res., November 1, 2003; 63(21): 7089 - 7093. [Abstract] [Full Text] [PDF]

				F. A. Feltus, E. K. Lee, J. F. Costello, C. Plass, and P. M. Vertino Predicting aberrant CpG island methylation PNAS, October 14, 2003; 100(21): 12253 - 12258. [Abstract] [Full Text] [PDF]

				T. Fan, Q. Yan, J. Huang, S. Austin, E. Cho, D. Ferris, and K. Muegge Lsh-deficient Murine Embryonal Fibroblasts Show Reduced Proliferation with Signs of Abnormal Mitosis Cancer Res., August 1, 2003; 63(15): 4677 - 4683. [Abstract] [Full Text] [PDF]

				P. Klatt and M. Serrano Engineering cancer resistance in mice Carcinogenesis, May 1, 2003; 24(5): 817 - 826. [Abstract] [Full Text] [PDF]

				T. H. BESTOR Unanswered Questions about the Role of Promoter Methylation in Carcinogenesis Ann. N.Y. Acad. Sci., March 1, 2003; 983(1): 22 - 27. [Abstract] [Full Text] [PDF]

				M. VERMA, B. K. DUNN, S. ROSS, P. JAIN, W. WANG, R. HAYES, and A. UMAR Early Detection and Risk Assessment Proceedings and Recommendations from the Workshop on Epigenetics in Cancer Prevention Ann. N.Y. Acad. Sci., March 1, 2003; 983(1): 298 - 319. [Abstract] [Full Text] [PDF]

				P. M. Campbell and M. Szyf Human DNA methyltransferase gene DNMT1 is regulated by the APC pathway Carcinogenesis, January 1, 2003; 24(1): 17 - 24. [Abstract] [Full Text] [PDF]

				J. Trasler, L. Deng, S. Melnyk, I. Pogribny, F. Hiou-Tim, S. Sibani, C. Oakes, E. Li, S. J. James, and R. Rozen Impact of Dnmt1 deficiency, with and without low folate diets, on tumor numbers and DNA methylation in Min mice Carcinogenesis, January 1, 2003; 24(1): 39 - 45. [Abstract] [Full Text] [PDF]

				R. Koratkar, E. Pequignot, W. W. Hauck, and L. D. Siracusa The CAST/Ei Strain Confers Significant Protection against ApcMin Intestinal Polyps, Independent of the Resistant Modifier of Min 1 (Mom1R) Locus Cancer Res., October 1, 2002; 62(19): 5413 - 5417. [Abstract] [Full Text] [PDF]