Altered Ten Eleven Translocation Methylcytosine Dioxygenase Expression and DNA Hydroxymethylation in a Mouse Model of Prostate Cancer.

BACKGROUND

DNA hydroxymethylation (5hmC) is known to be altered in human prostate cancer. An animal model is required to study the functional roles of the ten eleven translocation (TET) DNA dioxygenases and the 5hmC modification in prostate cancer development and progression.

METHODS

We characterized Tet expression, global genomic 5hmC, and genome-wide 5hmC patterns, and the transcriptome, in the TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) autochthonous model of prostate cancer.

RESULTS

We observed increased mRNA and protein levels of Tet1 in TRAMP samples, as compared to normal mouse prostate. Additionally, we found minimal expression of Tet2 mRNA overall, and Tet3 mRNA levels appeared similar in both sample types. However, TRAMP tumors expressed what appeared to be the inactive form of Tet3, versus the active form expressed in normal prostates. TRAMP tumors displayed global genomic hypohydroxymethylation (i.e., loss of 5hmC), and genome-wide analysis revealed widespread hypohydroxymethylation was interspersed with regions of locus-specific hyperhydroxymethylation (i.e., increased 5hmC). The differentially hydroxymethylated regions correlated with altered gene expression, and pathway analyses indicated that these genes often participate in oncogenic pathways.

CONCLUSIONS

Tet expression and 5hmC patterns are altered in the TRAMP model and closely match what has been observed in human prostate cancer, suggesting that TRAMP is a suitable model to study the role of Tets and 5hmC in prostate cancer development and progression.