Cancer Research Infection and Cancer: Biology, Therapeutics, and Prevention Joint Metastasis Research Society-AACR Conference on Metastasis
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by McCabe, M. T.
Right arrow Articles by Day, M. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McCabe, M. T.
Right arrow Articles by Day, M. L.
[Cancer Research 66, 385-392, January 1, 2006]
© 2006 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Inhibition of DNA Methyltransferase Activity Prevents Tumorigenesis in a Mouse Model of Prostate Cancer

Michael T. McCabe1,3, Jonathan A. Low2, Stephanie Daignault1, Michael J. Imperiale2,3, Kirk J. Wojno1 and Mark L. Day1,3

Departments of 1 Urology and 2 Microbiology and Immunology and 3 Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Mark L. Day, Department of Urology, University of Michigan, 6219 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0944. Phone: 734-763-9968; Fax: 734-647-9271; E-mail: mday{at}umich.edu.

Transcriptional silencing of tumor suppressor genes by DNA methylation plays an important role in tumorigenesis. These aberrant epigenetic modifications may be mediated in part by elevated DNA methyltransferase levels. DNA methyltransferase 1 (DNMT1), in particular, is overexpressed in many tumor types. Recently, we showed that Dnmt1 is transcriptionally regulated by E2F transcription factors and that retinoblastoma protein (pRb) inactivation induces Dnmt1. Based on these observations, we investigated regulation of Dnmt1 by polyomavirus oncogenes, which potently inhibit the pRb pocket protein family. Infection of primary human prostate epithelial cells with BK polyomavirus dramatically induced Dnmt1 transcription following large T antigen (TAg) translation and E2F activation. For in vivo study of Dnmt1 regulation, we used the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which expresses the SV40 polyomavirus early region, including TAg, under control of a prostate-specific promoter. Analysis of TRAMP prostate lesions revealed greatly elevated Dnmt1 mRNA and protein levels beginning in prostatic intraepithelial neoplasia and continuing through advanced prostate cancer and metastasis. Interestingly, when TRAMP mice were treated in a chemopreventive manner with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza), 0 of 14 mice developed prostate cancer at 24 weeks of age, whereas 7 of 13 (54%) control-treated mice developed poorly differentiated prostate cancer. Treatment with 5-aza also prevented the development of lymph node metastases and dramatically extended survival compared with control-treated mice. Taken together, these data suggest that Dnmt1 is rapidly activated by pRb pathway inactivation, and that DNA methyltransferase activity is required for malignant transformation and tumorigenesis. (Cancer Res 2006; 66(1): 385-92)




This article has been cited by other articles:


Home page
 CarcinogenesisHome page
W. Ji, L. Yang, L. Yu, J. Yuan, D. Hu, W. Zhang, J. Yang, Y. Pang, W. Li, J. Lu, et al.
Epigenetic silencing of O6-methylguanine DNA methyltransferase gene in NiS-transformed cells
Carcinogenesis, June 1, 2008; 29(6): 1267 - 1275.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Yamashita, S. Takahashi, N. McDonell, N. Watanabe, T. Niwa, K. Hosoya, Y. Tsujino, T. Shirai, and T. Ushijima
Methylation Silencing of Transforming Growth Factor-{beta} Receptor Type II in Rat Prostate Cancers
Cancer Res., April 1, 2008; 68(7): 2112 - 2121.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
A. J. Najy, K. C. Day, and M. L. Day
ADAM15 Supports Prostate Cancer Metastasis by Modulating Tumor Cell-Endothelial Cell Interaction
Cancer Res., February 15, 2008; 68(4): 1092 - 1099.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. M. Huffman, W. E. Grizzle, M. M. Bamman, J.-s. Kim, I. A. Eltoum, A. Elgavish, and T. R. Nagy
SIRT1 Is Significantly Elevated in Mouse and Human Prostate Cancer
Cancer Res., July 15, 2007; 67(14): 6612 - 6618.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
A. M. Sargeant, R. D. Klein, R. C. Rengel, S. K. Clinton, S. K. Kulp, Y. Kashida, M. Yamaguchi, Xingya Wang, and C.-S. Chen
Chemopreventive and Bioenergetic Signaling Effects of PDK1/Akt Pathway Inhibition in a Transgenic Mouse Model of Prostate Cancer
Toxicol Pathol, June 1, 2007; 35(4): 549 - 561.
[Abstract] [PDF]

Home page
 Clin. Cancer Res.Home page
A. P. Kumar, S. Bhaskaran, M. Ganapathy, K. Crosby, M. D. Davis, P. Kochunov, J. Schoolfield, I-T. Yeh, D. A. Troyer, and R. Ghosh
Akt/cAMP-Responsive Element Binding Protein/Cyclin D1 Network: A Novel Target for Prostate Cancer Inhibition in Transgenic Adenocarcinoma of Mouse Prostate Model Mediated by Nexrutine, a Phellodendron Amurense Bark Extract
Clin. Cancer Res., May 1, 2007; 13(9): 2784 - 2794.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
C. S. Zorn, K. J. Wojno, M. T. McCabe, R. Kuefer, J. E. Gschwend, and M. L. Day
5-Aza-2'-Deoxycytidine Delays Androgen-Independent Disease and Improves Survival in the Transgenic Adenocarcinoma of the Mouse Prostate Mouse Model of Prostate Cancer
Clin. Cancer Res., April 1, 2007; 13(7): 2136 - 2143.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. R. Morey, D. J. Smiraglia, S. R. James, J. Yu, M. T. Moser, B. A. Foster, and A. R. Karpf
DNA Methylation Pathway Alterations in an Autochthonous Murine Model of Prostate Cancer
Cancer Res., December 15, 2006; 66(24): 11659 - 11667.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
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]

Home page
 Molecular Cancer TherapeuticsHome page
B. A. Teicher
Tumor models for efficacy determination.
Mol. Cancer Ther., October 1, 2006; 5(10): 2435 - 2443.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. Shukeir, P. Pakneshan, G. Chen, M. Szyf, and S. A. Rabbani
Alteration of the Methylation Status of Tumor-Promoting Genes Decreases Prostate Cancer Cell Invasiveness and Tumorigenesis In vitro and In vivo.
Cancer Res., September 15, 2006; 66(18): 9202 - 9210.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
B. Cadieux, T.-T. Ching, S. R. VandenBerg, and J. F. Costello
Genome-wide Hypomethylation in Human Glioblastomas Associated with Specific Copy Number Alteration, Methylenetetrahydrofolate Reductase Allele Status, and Increased Proliferation.
Cancer Res., September 1, 2006; 66(17): 8469 - 8476.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
Copyright © 2006 by the American Association for Cancer Research.