DNA methylation pathway alterations in an autochthonous murine model of prostate cancer

Shannon R. Morey, Dominic J. Smiraglia, Smitha R. James, Jihnhee Yu, Michael T. Moser, Barbara A. Foster, Adam R. Karpf

Research output: Contribution to journalArticle

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Abstract

We examined the DNA methylation pathway in an autochthonous murine prostate cancer model, transgenic adenocarcinoma of mouse prostate (TRAMP). We observed that, compared with strain-matched normal prostates, primary and metastatic TRAMP tumors display increased cytosine DNA methyltransferase (Dnmt) activity, Dnmt1 and Dnmt3b protein expression, and Dnmt1, Dnmt3a, and Dnmt3b mRNA expression. Increased expression of Dnmt genes correlates with increased expression of cyclin A and E2F target genes, implicating increased cell proliferation and Rb inactivation in Dnmt overexpression. We analyzed DNA methylation in TRAMP and found that global levels of 5-methyl-2′- deoxycytidine are unaltered, whereas specific tumors display centromeric repeat hypomethylation. To interrogate locus-specific methylation, we did restriction landmark genomic scanning (RLGS) on normal prostates and primary tumors. In primary tumors, 2.3% of ∼1,200 analyzed loci display aberrant DNA hypermethylation, whereas a considerably smaller number of events show hypomethylation. The pattern of RLGS changes was nonrandom, indicating a coordinated methylation defect. Two specific genes identified by RLGS were studied in detail. Surprisingly, methylation of a downstream exon of p16(INK4a) (p16) was the highest frequency hypermethylation event identified in TRAMP, where it is associated with increased p16 mRNA and protein expression. In contrast, hypermethylation of the 5′ CpG island region of the homeobox gene Irx3 in TRAMP is associated with reduced gene expression. In summary, our data reveal a systemic DNA methylation pathway defect in TRAMP reminiscent of human prostate cancer, supporting the use of this model to investigate the functional role of DNA methylation pathway alterations in prostate cancer development.

Original languageEnglish (US)
Pages (from-to)11659-11667
Number of pages9
JournalCancer Research
Volume66
Issue number24
DOIs
StatePublished - Dec 15 2006

Fingerprint

DNA Methylation
Prostate
Prostatic Neoplasms
Transgenic Mice
Adenocarcinoma
Methyltransferases
Methylation
5-methyldeoxycytidine
DNA
Neoplasms
Genes
Cyclin A
Messenger RNA
CpG Islands
Homeobox Genes
Cytosine
Exons
Proteins
Cell Proliferation
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Morey, S. R., Smiraglia, D. J., James, S. R., Yu, J., Moser, M. T., Foster, B. A., & Karpf, A. R. (2006). DNA methylation pathway alterations in an autochthonous murine model of prostate cancer. Cancer Research, 66(24), 11659-11667. https://doi.org/10.1158/0008-5472.CAN-06-1937

DNA methylation pathway alterations in an autochthonous murine model of prostate cancer. / Morey, Shannon R.; Smiraglia, Dominic J.; James, Smitha R.; Yu, Jihnhee; Moser, Michael T.; Foster, Barbara A.; Karpf, Adam R.

In: Cancer Research, Vol. 66, No. 24, 15.12.2006, p. 11659-11667.

Research output: Contribution to journalArticle

Morey, SR, Smiraglia, DJ, James, SR, Yu, J, Moser, MT, Foster, BA & Karpf, AR 2006, 'DNA methylation pathway alterations in an autochthonous murine model of prostate cancer', Cancer Research, vol. 66, no. 24, pp. 11659-11667. https://doi.org/10.1158/0008-5472.CAN-06-1937
Morey SR, Smiraglia DJ, James SR, Yu J, Moser MT, Foster BA et al. DNA methylation pathway alterations in an autochthonous murine model of prostate cancer. Cancer Research. 2006 Dec 15;66(24):11659-11667. https://doi.org/10.1158/0008-5472.CAN-06-1937
Morey, Shannon R. ; Smiraglia, Dominic J. ; James, Smitha R. ; Yu, Jihnhee ; Moser, Michael T. ; Foster, Barbara A. ; Karpf, Adam R. / DNA methylation pathway alterations in an autochthonous murine model of prostate cancer. In: Cancer Research. 2006 ; Vol. 66, No. 24. pp. 11659-11667.
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